2alpha-methyl-6-dehydro steroids, 21-esters thereof and intermediates



U it d State at n Zoz-METHYL-G-DEHYDRO STEROIDS, ZI-ESTERS THEREOF AND INTERMEDIATES J Allan Campbell, Kalamazoo, John C. Babcock, Portage Township, Kalamazoo County, and John A. Hogg, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Filed Mar. 29, 1956, Ser. No. 574,614 8 Claims. (Cl. Mil-397.45)

OHiO R CH3 OH A1] R,

wherein R is selected from the group consisting of hydrogen and acyl in whichthe acyl radicalis of'an-organic carboxylic acid, preferably. a hydrocarbon carboxylic acid containingv from one to eightncarbon atoms, inclusive, R is a lower-alkyl containing from one to eight carbon atoms, inclusive, M is an alkali. metal of'; atomic weight6 thru 41, and X is a halogen of atomic weight 3 3thru130..

.The process of the instant invention comprises: treating a 21-esterof 1l 3,2lrdihydroxy-4,6,17(20):[cis]-pregnatrien-3-one(I) with .a lower alkyl esterof oxalic acid in the presence of an alkali-metal -base;to give .the correspondingalkali metal enolate vof- 2-lower-alkyloxyoxalyl- 11/8,21-dihydroxy-4,6,11(20)-[cis]-pregnatrien-Smne(LI). The alkali metal enolate (II) of;.its 2l-esters -produced by esterification in conventional manner, such ;as ,with anhydride or halides ororganic carboxylic acids, preferably hydrocarbon carboxylic acids containing from one to eight carbon atoms, inclusive,; is thereupon treated: with a lower alkyl bromide! or iodide; tosgive :a 2-loweralkyloxyoxalyl 2 loweralkyl 1113,21- dihydroxy- 4,6,17(20)-[cis]-pregnatrien-3-one or the corresponding 21-ester thereof (III), which is hydrolyzed withanalkali base, such as an alkali alkoxide to give 2-lower-alkyl- 115,21 dihydroxy 4,6,17(20) [cis],- pregnatrien- 3-one (*IV), Esterification of (IV) is productive of the 21-ester, 2 lower alkyl 11B -'hy,droxy- 21 acyloxy- 4,6,17(20)-[cis]*pregnatrien-3 one (V). The ester (V) is thereupon treated with osmium tetroxide 'in the presence of a. peroxide, such ashydrogen peroxide or; an amine oxide peroxide, such as N-methylmorpholine oxide peroxide tovgive 2-lower-alkyl-1;1p,17a,21-trihydroxy- 4,6-pregnadien-3,20-dione .21-acylatel (VI). Compound (VI) by hydrolysis'in a mildly alkali medium (preferably in a nitrogenatmosphere) provides the freetriol, 2 -loweralkyl 11,B,17a,21 trihydroxy r 4,6 :1 pregnadien: 3,20- dione which can be esteri-fiedin conventional manner to provide 2-lower-alkyl-11fi;17a-dihydroxy-21-acyloxy-4,6- pregnadiene-3,20-dione. Oxidation of .thisester with chromic acid produces 2-lower-alkyl 17a-hydroxy-Z17acyloxy- 4,6-pregnadien-3,11,20-trione. Dehydration of .2-loweralkyl 11/3,17a,21 t rihydroxy 4,6 pregnadiene 3,29- dione 21-acylate, illustratively with a hypohalous acid and anhydrous sulfur dioxide produces 2-lo ,w er-alkyl-17ahydroxy- 21 acyloxy 4,6,9'(11) pre'gnatriene- 3,20-

3 dione (VII). Addition of a hypohalous acid such as hypochlorous or hypobromous acid to the thus-obtained 2- lower alkyl 17oz hydroxy 21 acyloxy 4,6,9(11)- pregnatriene-3,20-dione results in 2-lower-alkyl-9a-halo- 115,17a dihydroxy 21 acyloxy 4,6 pregnatriene- 3,20-dione (VIII) which by treatment with a base such as anhydrous potassium acetate yields the epoxy compound, 2 lower alkyl 95,115 epoxy 17a hydroxy- 2l-acyloxy-4,6-pregnadiene-3,20-dione (IX). Treatment of the epoxy compound (IX) with hydrogen fluoride or other hydrogen fluoride releasing agents provides the active fluoro derivative, Z-IOWBI-alkYl-9oz-flll0f0-11{3,l7bbdihydroxy 21 acyloxy 4,6 pregnadiene 3,20 dione (X). Oxidation of, compound (X) with chromic acid in acetic acid provides the 2-lower-alkyl-9a-fluoro-170thydroxy-21-acyloxy-4,6-pregnadiene,3,l 1,20-trione (XI) Oxidation of compound VIII in the same manner as compound X results in other 2-lower-alkyl-9a-halo-17a, hydroxy-21-acyloxy-4,6-pregnadiene-3,1 1 ,20trione wherein halo is chloro, bromo, or iodo. Hydrolysis of the esters provides the free alcohols of these compounds which are useful either per se or as intermediates to produce by reesterification more desirable esters of the free alcohols,

such as 21-monoesters of 2-lower-alkyl-llB,17a,21-trihydroxy 4,6 pregnadiene 3,20 dione, 2 lower alkyl- 17a,21 dihydroxy 4,6 pregnadiene -'3,l1,20 triones and their 9a-halo derivatives.

It is an object of the present invention to produce certain 2-substituted 3 keto 11 oxygenated 4,6- pregnadienes. It is a particular object of the present invention to produce 2-lower-alkyl-1l 8,21-dihydroxy-4,6, 17(20) [cis] pregnatriene 3,20 dione, 2 loweralkyl 11B hydroxy 21 acyloxy 4,6,17(20) [cis]- pregnatriene 3,20 dione, 2 lower alkyl 170a hydroxy 21 acyloxy 4,6 pregnadiene 3,11,20 trione, '2-- lower alkyl 1701,21 dihydroxy 4,6 pregnadiene 3,11,20 --trione, 2 lower alkyl 9a halo- 115,170: dihydroxy 21 acyloxy 4,6 pregnadiene- 3,20 dione, 2 lower alkyl 90c halo 17a hydroxy- 21 acyloxy 4,6 pregnadiene 3,11,20 trione, and 2- lower alkyl 9oz halo 170:,21 dihydroxy 4,6 preg- 'nadiene 3,11,20 trione wherein the lower-alkyl contains from one to eight carbon atoms, inclusive; the acyl radical is "of an organic carboxylic acid, preferably of a hydrocarbon carboxylic acid, containing from one to eight carbon atoms, inclusive, and halo denotes the halogen atoms of atomic weight 17 thru 130, inclusive. It is another object of the instant invention to provide a process for the production of the intermediates of such 2- substituted-3-keto-ll-oxygenated-4,6-pregnadienes, especially the c'ompoundindicated by Formulae II thru V, inclusive and VII and IX. 'Other objects will be apparent tothose skilled in the art to which this invention pertains;

The compounds of the instant invention are important intermediates inthe production of highly active adrenal cortical hormones andin addition possess activity per se. For example, selective hydrogenation of 2-rnethyl- 115,17 dihydroxy 21 acyloxy- 4,6 pregnadiene- 3,20-dione, dissolved in methanol, in the presence of a five percent palladium-charcoal catalyst and potassium hydroxide, as shown in US. Patent 2,697,106, produces the highly active Z-methylhydrocortisone, while similarly selective hydrogenation of 2-lower-alkyl-9rx-halo-115,171;-

dihydroxy-21-acyloxy-4,6-pregnadiene-3,20-dione and hydrolysis produces the extremely active series of aldosterone-like and highly antiphlogistic 2-alklated-9a-halohylogs, such. as 2-lower-alkyl-l7a-hydroxy-2l-acyloxy-4,6-

pregnadiene-3,lil,20 tri0ne and theco rresponding 9a-halo dro'cortisones, of which the 2-methyl-9a-fluoro-hydrocorcompounds thereof, such as the 2-methyl-9 -fiuoro-17ahydroxy- 21 ac'yloxy 4,6 pregnadiene ,3,11,20-

trione providesthe corresponding Z-methylcortisone and 2 methyl c fluoro cortisone 2l-esters respectively. All of these compounds are important adrenal cortical steroids having pronounced adrenal hormonelike activity such as liver glycogen deposition, with few side reactions. While the chloro, bromo, and iodo derivatives of these 2-alkylated cortisone and hydrocortisone com pounds have activity of considerable significance, the greatest activity has been found in those having in the 9a-position a fluorine atom. The 2-methylllfi,l7a,2ltrihydroxy 4,6 pregnadiene 3,20 dione per se and the 21-esters thereof as well as the 2-methyl-9a-fluoro- 11,8,l70,21-trihydroxy-4,6-pregnadiene-3,20-dione and the esters thereof have adrenocortical hormonal activity particularly glucocorticoid activity greater than hydrocortisone. Similarly the corresponding ll-keto analogs, 2- methyl l7a,21 dihydroxy 4 pregnene 3,11,20 trione and the halo compounds such as 2-methyl-9a-fluoro- 17a,21-dihydroxy 4 pregnene-3,11,20-trione and esters thereof are useful as cortical hormonal agents in the same manner as the corresponding llfi-hydroxy analogs. These compounds also show mineral corticoid activity and anti-inflammatory activity.

The anti-inflammatory activity render these steroids particularly valuable for topical use such as dermatological and ophthalmic ointments or therapeutic dentifrices. A suitable dermatological and ophthalmic ointment illustratively has the following composition:

Lbs.

Wool fat USP Mineral oil USP 2 methyl 9oz fluoro 11,8,17u dihydroxy 21- acetoxy 4,6 pregnadiene 3,20 dione (micronized) 1.5 White petrolatum USP, q.s.-ad 500 Incorporation of an antibiotic in the intment, especiallly neomycin sulfate, has surprising therapeutic advantage, each active ingredient potentiating and supplementing the useful properties of the other. Such an ointment is as follows:

Lbs. Wool fat USP 100 Mineral oil USP 125 Neomycin sulfate (microatomized) 0.5

2 methyl 9a fluoro 115,17a dihydroxy 21- acetoxy 4 pregnene 3,20 dione (micronized) 1.5

White petrolatum USP, q.s.-ad 500 Lbs. Precipitated calcium carbonate 400 Titanium oxide 50 Distilled water 450 Methyl cellulose 10 Sodium lauryl sulfate Q 30 Glycerine 50 Methyl para-hydroxybenzoate 1 2 methyl. 90c fiuoro 115,17a dihydroxy 21- acetoxy 4,6 pregnadien 3 one 1 Cinnamon oil 4 Peppermint oil 2 Spearmint oil 2 To prepare this therapeutic dentifrice, methyl parahydroxybenzoate is dissolved in parts of boiling Water and poured over the methyl cellulose. While the mass swells and softens stirring is continued until cool. Thereupon the remainder of the water is added, then in the stated order the glycerin, calcium carbonate and titanium-oxide, the sodium lauryl sulfate and the steroid. Homogeneity is improved my rnillings and thereupon the flavoring is incorporated. Obviously other flavoring may be used. Inaddition saccharine may be used for sweetening (from 0.5 to 1 part per 1000 parts of dentifrice). The titanium oxide may if desiredbe substituted by calcium carbonate or dicalcium phosphate. Other ingredients, such as antibiotics, for example, neomycin, penicillin, tetracycline, or the like, can be added and the particular steroid, 2-methyl-9a-fluoro-1lp,l7a-dihydrcxy- 2l-acetoxy-4,6-pregnadien-2-one may be substituted by other v2.-alkyl-l1,17-oxygenated-4,6 pregnadien 3 ones such as shown and produced in Examples 11 thru 14, 18, 20, 22 and 26 thru 33. Theamount of steroid in the dentifrice may be up to 0.5 percent for the fluoro substituted steroids in this disclosure and up to 2.5 percent for the other halogenated or non-halogenated steroid shown in the examples.

A dental ointment useful for topical application in cases of desquamat-ive gingivitis can be prepared as described below:

Percent White petrolatum USP 94% White wax USP M.P. (61-65 C.) 5%

2-methyl-9a-fluoro-11fi,17a-dihydroxy-21 acetoxy- 4,6-pregnadiene-3,20 dione 0.2% Flavoring oil 0.8%

The White Wax and white petrolatum are melted'and stirred until the temperature reaches fifty degrees centigrade. The micronized steroid and the flavoring oil are added and the ointment is allowed to cool with continuous vigorous stirring until it congeals. The congealed mixture is then milled to achieve greater uniformity,

Instead of 2-methyl-9a-fluoro-11,B,l7u-dihydroxy-21- acetoxy-4,6-pregnadiene-3,20-dione, other steroids such as described in Examples 11 thru 14, 18, 20, 22, and 26 thru 33 may be used, usually in amounts from 0.05 to 0.5 percent for the fiuoro steroids and from 0.1 to 2.5 percent for the other halo or non-halogenated steroids. Additionally, antibiotics, such. as for example, neomycin, bacitracin, tetracycline, Aureomycin, Terramycin, or the like, and/or ,sulfonamides may be incorporated in this ointment. The starting materials for the instant process are 1 1B,21-dihydroxy-4,6, 17 (20)-[cis]-pregnatrien-3-one 2l-acylates such as the 21-acetate, or the free alcohol. 1 15,2 l -dihydroxy-4,6, 17 20) [cis] -pregnatrien-3-one and the 21-esters thereof are prepared by methods such as shown in Preparations 1 thru 7.

In carrying out the process of the present invention, 11p,21-dihydroxy-4,6,17(20)-[cis]-pregnatrien-3-o-ne or ,a selected 21-ester thereof is admixed with a selected alkali metal condensation catalyst and a dialkyl ester of oxalic acid in an organic solvent. The order of mixing to .produce the alkali-metal salt of the compound represented by Formula II is not critical. Reaction solvents which can conveniently be employed in the condensation, include benzene, toluene, xylene, and the like aromatic hydrocarbons, methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol, and other alcohols, tetrahydrofuram dioxane, diethyl ether, Skellysolve B hexane hydrocarbons, and other aliphatic hydrocarbons, mixtures of these solvents and other essentially unreactive solvents. Benzene, with or without small percentages of added alkanol, or tertiary butyl alcohol are usually the preferred solvent. The preferred condensation agent is a lower-alkyl oxalic acid ester such as methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, phenyl, benzyl, or the like oxalic acid esters, with methyl and ethyl oxalate preferred. The condensation is generally conducted at a temperature between about Zero degrees-Centigrade and the boiling point of the reaction mixture. The reaction proceeds with satisfactory. .rapidity at. between about room.v temperature (twenty to thirty degrees centigrade) and-about seventy 6 degrees centigrade, and temperatures substantially above or below thisrange are therefore not required, The time necessary to obtainsub stantially complete reaction varies considerably, between about five minutesand several days, depending upon the reaction solvent, the reaction temperature, the selected ester of oxalic acid and the alkali rnetal condensation catalyst employed. When methyl orethyl' oxalate and tertiary butyl alcohol are employedat about fifty degrees centigrade, the reaction is usually more than half completed in a few minutes, The condensation step is preferably carried outin the absence ofanysignificant amounts of water. To insure the essentiallycomplete exclusion ofv Water from thereactionmixture, the solvent is carefully dried with a drying agent, such as, for example, anhydrous sodium sulfate,.calcium sulfate, calcium chloride, phosphorus pentoxid e, sodium, or the like, or when an aromatic hydrocarbon is used as a solvent, a portion of the solvent is distilled before using.

Alkali metal condensation catalysts include the alkali metal alkoxides, wherein the alkyl radical of the alkqxy group contains from one to eight carbon atoms, inclusive,

and wherein the alkali metal is of atomic weight six thru forty, such as sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium tertiary butoxide, lithium meth-oxide, and the like, the alkali metals,.tl ie alkalii metal hydrides, alkali metal amides f g, sodium alkyl alkali metals, for example, triphenylmethylsodium, and the like, Of these, the alkali. .metal alkoxides especially sodium methoxide and sodium ethoxide'are pre ferred for their convenience and consistentlysatisfactory results. The alkali metalalkoxidesmay be {usedsolventfree, dissolved or suspended in a non-reactive solvent, or in situ in the alkanol in which said alkali metail alko xide was prepared. Potassiumis conveniently used as the solution formed by its reaction with tertiary butyl alcohol according to procedures well known in the art. The theoretical alkali metal condensation, catalyst required is one mole per mole of steroid. Somewhat more than the theoretical amount is usually employed. I k The thus produced alkali metal enolate may be separated by the addition of a large volume of an organic solvent in which the alkali metal enolate is. insoluble, such as ether, pentane, or benzene, for examp le, Ahother method of producing somewhat purer alkali metal eirolate comprises acidification of a cold aqueous solution ofthe thus precipitated alkali metal enolate to precipitatelhe free enol and then treating a solution ofthe free enol in ether or benzene with a chemical equivalent of sodium methoxide, thus reprecipitating the sodium errolate. When the condensation is carried out in the presence of a substantial amount of rnethyl or ethyl alcohol, removal of said alcohol by distillation at reduced pressure before the addition of an additional amount of solvent is; preferred, if a high yield of isolated product is to be obtained.

The thus produced alkali metal enolate of 2 -lowe r-alkyloxyoxalyl 115,21 dihydroxy 4,6,17( 20 -.[ois]; pregnatrien-3-one or the corresponding 2 1-ester thereof is alkylated by the addition of a lower alkyl halide, such as methyl iodide, ethyl iodide, propyl bromide, isopropyl iodide, butyl chloride, bromide andiodide, pentyl chloride, bromide, and iodide, hexyl, heptyl, and octyl chloride and bromides, allyl bromide, phenyl bromide and-iodide, benzyl chloride, bromide or iodide, and the like. I In the preferred embodiment the alkyl halide is added to the steroid, dissolved in an organic solvent, such as-methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, pentanes, hexanes, or the like. After adding the alkyl halide to the solution, the reaction is continued for several hours, for example, about eight to about 72 hours at a reaction temperature of aboutroom temperature, twenty to thirty degrees centigrade. Higher temperatures 'shorten this reaction time considerably. A convenient method of alkylation was the addition of the selected alkyl halide to the reaction productresulti ng from the condensation step, preferably after thedecomposition of V 7 7 any excess alkali metal condensation catalyst. Satisfactory yields are also obtained by stirring the solution of the free active methylene compound, the metal enolate of 2- 'alkoxyoxalyl 1119,21 dihydroxy 4,6,17(20) [cis]- hydroxy-4,6,17 (20) [cis] -pregnatrien-3one is obtained.

The reversal step of the present invention involves the removal of the alkoxyoxalyl group from the 2-position leaving the alkyl group at the 2-position thus producing a 2 lower -,alkyl 115,21 dihydroxy 4,6,17(20) [cislpregnatrien-3-one or the respective 21-ester thereof. The reversal step of .the present invention is produced by the alkali metal alkylation catalyst, sodium or potassium car- .bonate, in the presence of water or a lower-alkanol. The reversal reaction is especially promoted by the presence of hydroxide or alkoxide, particularly rnethoxide and ethoxide ions. After reacting the 2-alkyloxyoxalyl-2-alkyl 11 ,21 dihydroxy 4,6,17(20) [cis] pregnatrien- 3-one or a 21 ester thereof with a base such as methanol and sodium methoxide, ethanol and sodium ethoxide or methoxide at room temperature, the mixture is poured 'into a large amount of water and the product is separated by conventional means such as extraction, filtration, or the like, and the material, a 2-alkyl-11;8,21-dihydroxy- 4,6,17(20)-[cis]-pregnatrien-3-one (or a 21-ester thereof), is purified by recrystallization, additional extraction 'of impurities, chromatography, or the like, as deemed necessary.

The 21-acyloxy group of a 2-lower-a1kyloxyoxa1yl-2- alkyl 11,8 hydroxy 21 acyloxy 4,6,17(20) [20]- pregnatrien-3-one is removed in the reversal reaction if the acyl group is of a simple unhindered acid such as acetic, propionic, or the like. If the acyl group is of a sterically hindered acid such as dineopentylacetic, trimethylacetic, or the like, the 21-ester group remains intact. In many other cases, a mixture of the ester and the free alcohol is obtained. If desired, the ester is reformed by conventional procedure, such as reacting the obtained 2 5 lower alkyl 1l,8,21 dihydroxy 4,6,17(20) [cis]- pregnatrien-3-one with an acid anhydride or acid halide of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, in pyridine or in a neutral organic solvent such as benzene, toluene, or the like.

The thus obtained 2-1ower-alkyl-115,21-dihydroxy- 4,6,,17(20)-[cis]-pregnatrien-3-one or the 21-acyloxy esters thereof is hydroxylated with an hydroxylating agent and an oxidizing agent to give the corresponding 2-loweralkyl-115,170:,21-trihydroxy-4,6-pregnadiene-3,20-dione.

The hydroxylation of a A -21-acyloxy steroid to produce a 17a,20 dihydroxy steroid is a well known reaction (see, for example, Ruzicka and Mueller, Helv. Chim. 'Acta, 22, 57 (1939) and US. Patent 2,492,194). In this reaction, a metal oxide is ordinarily employed to add to the double bond to produce, upon hydrolysis, a glycol. Osmiumtetroxide is the metal oxide of choice. For a discussion of the hydroxylating abilities of the metal oxides, preferably from groups IV, V and VI of the periodic table, see Milas, J. Am. Chem. Soc. 59, 2342 (1937) and Mudgen and Young, J. Chem. Soc. 1944, 2988. Examples of such hydroxylating metal oxides or derivatives thereof include manganese dioxide, vanadium pentoxide,

chromium trioxide, pertungstic acid, permolybdic acid, selenium dioxide, etc.

The first recognized example of an oxidative hydroxylation of a steroid is found in Prins and Reichstein, Helv.

Chim. Acta, 25, 300 (1942), reporting the use of osmium tetroxide and chloric acid, for the oxidative hydroxylation offa A l b-steroidto produce :a 2O keto-21-hydroxy .steroid; i The concept of oxidative hydroxylation outside 8 the field of steroidal chemistry'was first demonstrated, with hydrogen peroxide, by Criegee, Annalen der Chemie, 522, (1936).

Oxidizing agents which may be employed in the oxidative hydroxylation step of the present invention are the oxidizing agents which contribute an oxygen atom to the reaction and include, hydrogen peroxide, alkyl peroxides, peracids, chloric acid, periodic acid, acetyl peroxide, benzoyl peroxide, tertiary amine oxide peroxides, aryliodo oxides, lead tetraacetate, manganese dioxide, mercury diacetate and the like oxygen donating agents. The use of osmium tetroxide and hydrogen peroxide in the oxidative hydroxylation of certain A -21-substituted steroids is claimed in US. Patents 2,662,854 and 2,668,816. The use of amine oxide-peroxides with osmium tetroxide in the oxidative hydroxylation of A -21-acyloxy steroids is claimed in the copending application of Schneider and Hanze, S.N. 425,315, filed April 23, 1954, and the use of aryliodo oxides with osmium tetroxide in the oxidative hydroxylation of these same steroids is claimed in the copending application of Schneider, S.N. 443,418, filed July 14, 1954. The use of hydrogen peroxide, an amine oxide peroxide or an aryliodo oxide as the oxidizing agent in the oxidative hydroxylation of the present invention is preferred. The use of these reagents is discussed more fully below.

The amine oxide peroxides which may be employed in the oxidative hydroxylation step of this invention are prepared by the reaction of some tertiary amines with two molar equivalents of hydrogen peroxide or by the reaction of a tertiary amine oxide with one molar equivalent of hydrogen peroxide. Amine oxide peroxides are a novel class of oxidizing agents. For the most part, they have a higher oxidation potential than the hydrogen peroxide from which they are prepared.

The amine oxide peroxides of the present invention are preferably non-aromatic, i.e., the molecule is devoid of an aromatic group of any kind. The non-aromatic tertiary amine oxide peroxides include the N-alkylcyloalkylamine oxide peroxides, e.g., N-alkylrnorpholine oxide peroxide, N-alkylpyrrolidine oxide peroxides, and N- alkylpiperidine oxide peroxides, the trialkylamine oxide peroxides, e.g., trimethylamine oxide peroxide, triethylamine oxide peroxide, methyldiethylamine oxide peroxide, ethyldimethylamine oxide peroxides, the alkanolamine oxide peroxides, e.g., dimethylethanolamine oxide peroxide pyrrolidylethanol oxide peroxide, piperidylethanol oxide peroxide or the like. Of these amine oxide peroxides, triethylamine oxide peroxide and N-methylmorpholine oxide peroxide are especially advantageous.

The organic polyvalent iodo oxideswhich may be employed in the oxidative hydroxylation step of this invention are organic iodo compounds having at least one titratable oxygen atom attached to the iodine atoms. The presence of a titratable iodo oxide oxygen atom can be determined in the usual manner with KI, acid and sodium thiosulfate. The known examples of these iodo oxides are iodoso, iodyl and iodoxy compounds and salts thereof. The iodonium compounds are not included in the term iodo oxides as used herein since the hydroxy group of the iodonium compounds is ionic in nature and is not therefore directly attached to the iodine atom, but merely associated with it ionically. The iodoso compounds have one oxygen atom attached to the iodine atom; the iodoxy compounds have two oxygen atoms attached.

Many iodo oxides are disclosed in Willgerodt, Die Organischem Verbindungen Mit Mehrwertigem Jod, F. Enke, Stuttgart (1914). Other references include R. Sandin, Organic Compounds of Polyvalent Iodine, Chem. Rev. 32, 249 (1943); Sidgwick, Chemical Elements and Their Compounds, vol. II, 1243-1260, Oxford Univ. Press (1950); and Mason et al., J. Chem. Soc. 1669 (1935). The latter reference'discloses the iodyl compounds.

In accord with these references, iodo oxidescan be prepared from aryl iodo compounds or other vinyl iodides whose double bond is also modified in some way, e.g., by halogenation, as in a-chloro-iodoethylene, chloroiodofumaric acid or a-chloroeiodoacrylic acid.

Examples of the known aryl iodo oxides include iodosobenzene, phenyliodosoacetate, diphenyliodyl hydroxide andacetate, phenyliodosopropionate, iodoxybenzene, the ring alkylated iodoso and iodoxybenzenes, and the oxides of iodo-naphthylene, iodobenzoquinone and iodobenzaldehyde, .iodo-benzophenone, iodosalicylic acid, etc.

1 In carrying out the oxidative hydroxylation step of the invention, the starting steroid is advantageously dissolved in an inert organic solvent, for example, tertiary butyl alcohol, diethyl ether, tetrahydrofuran, or the like, and the hydroxylating agent preferably osmium tetroxide and the oxidizing agent mixed therein. Advantageously, though not necessarily, the hydroxylating agent is added after the addition of the oxidizing agent. Advantageously also, the osmium tetroxide and the oxidizing agent peroxide are added in solutions of the same solvent used as the vehicle for the reaction.

The amount of the preferred osmium tetroxide hydroxylating agent employed in the reaction can be varied widely, for example, from about 0.2 molar equivalent to 0.00l molar equivalent. Advantageously, however, not more than 0.05 molar equivalent is used.

The amount of oxidizing agent theoretically required to produce a 17-hydroxy-20-keto-2l-acyloxy steroid is two oxidizing equivalentsv for each mole of osmate ester formed in the reaction. It has been found, however, that in the process of this invention, more than the theoretical amount of oxidizing agent is ordinarily necessary to obtain a complete reaction. For optimum results in the process of this invention, therefore, it is usually desirable to use the oxidizing agent in excess of the theoretical amount. For example, optimum results are ordinarily obtained using between about 2.2 and about 2.75. equivalents of amine oxide peroxide or aryl iodo oxide, .calculated on the starting steroid. The course of the. oxidative hydroxylation reaction can be readily, determined by the titration of aliquot portions for residual oxidizing agent. Ordinarily, the presence of small amounts ofi w ater in the reaction mixture does not adversely affect the yield of desired product. However, to ensure optimum. yields of, desired product when employing hydrogen peroxide or an amine oxide peroxide, the reaction advantageously may be performed under substantially anhydrous conditions, e.g., in dry tertiary butyl alcohol, or like solvent. U

The reaction temperature for the oxidative hydroxylation step norm-ally is between about fifteen and about thirty degrees centigrade although higher or lower temperatures are operable, e.g., between about minus ten and about plus seventy degrees centigrade. In place of the-solvents noted. above, .there may be usedany inert solvent'whichis. a solvent for the reagents. Suitable solvents include diethylether, dioxane, isopropylalcohol, tetrahydrofuran, tertiary butyl alcohol, tertiary amyl alcohol, ethanol and. methanol. v

Hydrolysis of: this material by alkali, preferably in a nitrogen. atmosphere, produces the free triol, 2-loweralkyl 11fi,17oc,21 trihydroxy 4,6 pregnadiene 3,20- dione. Esterification of the triol with halides and hydrides of organic carboxylic acids or hydrocarbon .carboxylic acids containing from one to eight carbon atoms gives 2 lower alkyl 11fi,17cc dihydroxy 21.- acyloxy-4,6-pregnadiene-3,20-diones.

Oxidation of the 2-lower-alkyl-1l,B,17ot-dihydroxy-21- acyloxy-4,6-pregnadiene-3,20-dione with chromic acid is productive of the corresponding 2-lower-alkyl-17a-hydroxy-21-acyloxy-4,6-pregnadiene-3,1 1,20-trione.

Inorder to obtain the corresponding 9a-halo compounds, the 2 lower alkyl 11fi,17a,21 .trihydroxyi0 4,6-pregnadiene-3,20-dione 21-acy1ate is dehydrated to the corresponding 2-lower-al kyl-17a,21-dihydroxy-4,6,9(.11 pregnatriene-3,20-dione 21-acylate by methods known in the art. Suitable dehydrating agents are for example phosphorus oxychloride, hydrochloric acid, or sulfuric acid in acetic acid, or pyrolysis as shown by US. Patents 2,640,838 and 2,640,839. In the preferred embodiment of the present invention the dehydration is elfected by reacting the 11 fi-hydroxy compound with an N-haloamide or N-haloimide in an organic base and treating the thus produced intermediate ll -hypohalite with dry sulfur dioxide in an organic base. As reagents for the production of an ll-hypohalite, the N-haloamide or N-haloimide are used wherein the halogen has an atomic weight from 34 to 130, inclusive, preferably chlorine or bromine. Examples of such compounds are N-chloroacetamide, N- bromoacetamide, N chlorosuccinimide, N bromosuccinimide, N-iodosuccinimide, 3-bromo-5,5-dimethy1hydantoin and 1,3 dibromos5,5-dicethylhydantoin. Ordinarily an amount in excess of a molar equivalent, calculated on the starting llQ-hydroxy steroid, is employed. The base employed in the production of the ll-hypohalite is. a tertiary amine wherein the amino nitrogen is a member of an aromatic ring, for example, the pyridines, that is, pyridine, alkyl-pyridines, piccoline, lutidine, collidine, conyrine, parvuline, or the like, or lower fatty amides such as formarnide, methylformamide and dimethylformamide. The, base is preferably employed in alarge molar excess, calculated on the starting lle-hydroxy steroid, for example, ten molar equivalents, and is preferably the sole reaction solvent. The reaction to produce an ll-hypohalite is generally conducted under anhydrous conditions preferably containing less than 0.1 molar equivalent of water calculated per mole of steroid. Large proportionsof water decrease the yield. The temperature of the reaction is between minus forty and plus seventydegrees entigrade, the lower limit being determined by the solubility of the reaction and solvents and the upper limit being determined by the amount of side reaction. Ordinarily, room temperature (twenty to thirty .degrees centigrade) is preferred for convenience and the consistently high yields of the desired product which are obtained at this temperature. A reaction period between five minutes to three hours is usually employed. At higher temperatures, above thirty degrees centigrade, short reaction times are sufiicient to produce completeness of the reaction.

The thus produced 2-lower-alkyl-l1;3,17a,21-trihydroxy- 4,6-pregnadiene-3,20-dione 11,8-hypohalite 2l-acylate is then treated with anhydrous sulfur dioxide in the presence of an organic base as described hereinbefore. The anhydrous sulfurdoxide can be in the form of gaseous or liquid sulfur dioxide or in the form of a material which in situ produces sulfur dioxide, for example, alkali metal hyposulfite. The reaction temperature ranges substantially within minus forty and plus seventy degrees centigrade and preferably room temperature (twenty to thirty degrees centigrade). The thus obtained product, a 2-lower alkyl- 17 04,2 1 -dihydroxy-4,6,9 l 1 -pregnatriene- 3,20-dione 2l-acylate is isolated by conventional means such as extraction from the reaction mixture after the reaction mixture has been poured into excess of water. Organic water-immiscible solvents such as ether, chloroform, methylene chloride, carbon tetrachloride, ethyl acetate, benzene, hexanes, or the like, are used for the extraction, The thus obtained extracts are conveniently Washed, dried and thereupon evaporated to givethe halo acid amide or an N-halo acid imide with an acid to produce the hypohalous acid in situ. In the preferred embodiment of the invention, the steroid, a Z-alkyl- 170:,21 dihydroxy 4,6,9(11) pregnatn'ene 3,20- dione or the esters thereof is dissolved in an organic solvent such as methylene chloride, tertiary butyl alcohol, dioxane, tertiary amyl alcohol, or the like, and reacted at room temperature with the hypobromous or hypochlorous acid releasing agent in the presence of an acid.

Such hypohalous acid releasing agents include the N- bromoacetamide, the N-chloroacetamide, the N-bromosuccinimide, the N-iodosuccinimide, or the like, in the 'presence of water and an acid such as perchloric acid, dilute sulfuric acid, or the like. The reaction is usually carried out at room temperature, between fifteen to thirty degrees centigrade, however, lower or higher temperatures are operative for the process. The hypohalous acid releasing agent is generally used in one molar or slightly increased, for example 25 percent increased amounts compared to mole ofsteroid. A large excess of the hypohalous acid releasing agent while operative is undesirable since the excess of hypohalous acid has a tendency to react on other positions of the molecule. The reaction period is rather short and may vary between about four to five minutes to one hour. At the end of the reaction time excess of hypohalous acid is destroyed by the addition of sodium sulfite or other sulfites or hydrosulfites. The thus produced product, a 2-1ower-alkyl- 9a-halo-1 1B,1741-21-tl'lhYdTOXY-4,6-p1egnadlfi11e-3,ZO-dlone 21-acylate, wherein halo is of atomic weight between 33 and 130, is isolated from the reaction mixture by adding excess of water and extracting the compound with organic solvents or by recovering the precipitated compound through filtration. A crude product thus obtained may be recrystallized from acetone and Skellysolve B hexane hydrocarbons to give pure Z-lower-alkyl-9u-halo-115,17, 21-trihydroxy-4,6-pregnadiene-3,ZO-dione 21-acylate.

The halo ester thus obtained can be hydrolyzed in an alcoholic acid medium to give the free triol, 2-1oweralkyl 90c halo 1lB,17oc,21 trihydroxy 4,6 pregnadiene-3,20-dione, which upon reesterfication gives additional esters.

Oxidizing the 21-esterof a 2-lower-alkyl-9'a-halo-11B, flail-trihydroxy 4,6 pregnadiene 3,20 dione, with chromic acid produces the corresponding pharmaceuticali 1y active (aldosterone-like' and antiphlogistic) 2-loweralkyl-9u-halo-Hall-dihydroxy 4,6-pregnadiene-3,l1,20- trione 2l-acylate which by hydrolysis gives the free diol, 2-lower-alkyl-9a-halo-17a,2 1-dihydroxy 4,6-pregnadienc- 3,11,20-trione.

To obtain the 9ct-fll1OIO compounds, the 9,8-11B-e'poxy intermediates of the before-mentioned compounds, 2- lower alkyl 9,8,11fl epoxy 1704,21 dihydroxy- 4,6- pregnadiene-3,20-dione esters, are first prepared. In this reaction a 2-lower-alkyl-9a-halo 11B,17u,21-trihydroxy- 4,6-pregnadiene-3,ZO-dione ester is heated in solution with a mild base, and preferably in the absence of water to avoid hydrolysis of the ester groups.

The bases useful for the cyclization include anhydrous potassium acetate, sodium bicarbonate, sodium acetate, or the like, with potassium acetate preferred. Solvents such as methanol, ethanol, acetone, tertiary butyl alcohol, or the like, may be used; The reaction time is between one half hour and 24 hours; generally a period between three and twelve hours is suflicient. The thus obtained 2-loweralkyl 95,113 epoxy 1704,21 dihydroxy 4,6-pregnadiene-3,20-dione is isolated from the reaction mixture by pouring the reaction mixture into excess water and extracting with methylene chloride or other water-immiscible solvents; such as ether, Skellysolve B 'hexanes, pentanes, benzene, ether, ethyl acetate, chloroform','carbon chloroform, carbon tetrachloride or the like is useful, with methylene chloride preferred. As acid catalysts, perchloric acid, toluene-sulfonic acid, sulfuric acid or the like may be used. The reaction is carried out at room temperature (twenty to thirty degrees centigrade) preferably with stirring. The period of reaction is from one to 24 hours with a period from one to twelve hours usually sufficient. After the reaction is terminated, the mixture is poured into water and neutralized with a dilute base such as sodium bicarbonate, potassium bicarbonate, or the like. Excess of strong bases can also be used. The reaction mixture is then extracted with a water-immiscible solvent such as methylene chloride, the organic layer is separated from the water mixture, Washed with water, dried and evaporated to give the crude 2-10W6I-21lkYl-9a-flll0IO-llfl, 17a,2l trihydroxy 4,6 pregnadiene 3,20 dione 21- acylate. The thus obtained crude compound is purified through recrystallization or chromatography as deemed necessary.

The 2 lower alkyl 9oz fluoro l1 3,170c,21 trihydroxy 4,6 pregnadiene 3,20-dione esters obtained by this process can be hydrolyzed to give the 2-lower- 'alkyl 9oz fluoro 11}3,l7oa,21 trihydroxy 4,6 pregnadiene-3,20-dione which is esterified with acyl halides or acyl anhydrides in pyridine solution at room temperature to give the corresponding 21-esters of 2-lower-alkyl-9afluoro 11,8,17oc,21 trihydroxy 4,6 pregnadiene 3,20- dione.

Oxidation of the 2-l0wer-alkyl Qa-fluoro llfi,17a,21- trihydroxy 4,6 pregnadiene 3,20 dione 21 acylate with chromic acid produces the corresponding 2-loweralkyl c fluoro 17u-21 dihydroxy 4,6 -'pregnadiene 3,11,20-trione 21-acylate which is hydrolyzed with sodium bicarbonate in ethanol in a nitrogen atmosphere to give the free triol, 2-lower-alkyl-9a-fiuoro-17a-2Ldihydroxy- 4,6-pregnadiene-3,l1,20-t1ione., I V

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

PREPARATION 1' Methyl 3,1 1-di k et0-6-br0m0-4J 7(20 [cis] -pregnadien 21 -0ate .for four hours while bubbling nitrogen through the reaction mixture. The solvent was then removed by distillation at reduced pressure and the residue was triturated 'with ethyl acetate. The insoluble material was recrystal- -lized from ethyl acetate after decolorizing the solution with decolo'rizing charcoal. There was obtained 2.2 grams "of methyl 3-acetoxy-1l-keto-3,5,17(20) [cis] pregnatrien-21-oate melting at to degrees 'centigrade, having an 5 of 28,850 and an infrared spectrum consistent with the structure. 1

Methyl 3-11 diketo 4,l7(20) [cis] pregnadien-Zloate can be prepared according to the method disclosed in U.S. Patent 2,707,184. This compound is converted to the corresponding methyl 3,11 diketo-4,l7(20)-[trans]- pregnadien-Zl-oate by refluxing in. methanol containing sodium methoxide. The other alkyl 3,1 l-diketo-4,l7(20)- pr'eguadien-Zl-oates are similarly prepared. r

'bromo-acetamide, two grams of sodium acetate trihydrate and 2.2 milliliters of glacial acetic acid in forty milliliters of water. A precipitate of starting material formed and an additional 150 milliliters of acetone was added. The solution, was stirred at room temperature for three hours. The acetone was removed by distillation at reduced-pressure. The concentrate was diluted with ether and the ether solution was washed with an aqueous sodium bicarbonate .solution and then with water. The Washed solutionwas dried, filtered, and the filtrate distilled to dryness. Theresidueconsisted of methyl 3,11-diketo-6-bromo-4, 17(20)-[cis]-pregnadien-21-oate which melted at 133 to 140 degrees centigrade with decomposition, had an E2315 of 20,300, and the analysis below:

JCalculated for C H O Br: Br, 18.50. Found: Br,

" PREPARATION 3 Methyl 3,11 -diket-4,6 ,1 7(20) [cis] -pregnatrien-21-oate .silicate. The filtrate was concentrated to dryness and the residue triturated with ether. The insoluble material-was crystallized from methanol to give 13.6 grams of methyl 3,11 diketo-4,6,17()-[cis]-pregnatrien-2l-oate melting at 180 to 1 82 degrees centigrade. An analytical sample, obtained by recrystallization of the methyl 3,11-diketo- 4,6,17(20)-[cis] -pregnatrien-21-oate from acetone, melted -at 183 to 185 degrees centigrade, had an [0:1 of plus 228 degrees in acetone, an 6 of 14,050 and an 6 of 23,075. The ether and methanol mother liquors were combined and distilled to dryness. The residue was dissolved in benzene and poured over a column of 200 grams of Florisil. The column was developed with Skellysolve B containing increasing amounts of acetone. The Skellysolve B plus nine percent acetone to the Skellysolve B plus thirteen percent acetone eluates contained the desired product.

The eluted product consisted of a different crystalline form of the methyl 3,11-diketo-4,6,17(20)-[cis]-pregnatrien-21-oate which melted at 170 to 174 degrees centigrade. A mixture of the two forms melted at 183 to 185 degrees centigrade. This material analyzes as a solvate of acetone. After dryingthe product. at 100 degrees centigrade for several days, the molecule of acetone was lost and the product had the analysis below:

Calculated for C H O C, 74.55; H, 7.39. Found: C, 74.53; H, 7.12.

PREPARATION 4 Methyl 3 ,7-dipyrr0lidy L3 ,5 ,1 7(20) [cis] -pregnatrien- 21-0ate A solution of 19.0 grams (0.055 mole) of methyl 3,11- diketo-4,6,17(20)-[cis]-pregnatrien-21-oate and fifty milligrams of para-toluenesulfonic acid in a mixture of 69 milliliters of methylene chloride and nineteen milliliters of pyrrolidine were maintained at room temperature untion'to its boiling point.

14 der nitrogen for forty minutes. The mixture was distilled to dryness at reduced pressure and the residue was slurried with a small amount of methanol and the methanol distilled at reduced pressure. A small amount-of ether was addedwhich was also distilled at reduced pressure. The product was dried under high vacuum for about three hours. The thus-produced methyl 3,7-dipyrrolidyl 3,5,17(20) [cis] pregnatrien-21-oate had an ultraviolet absorption maximum at 324 me in methanol.

PREPARATION 5 3,7-dipyrrolidyl-l1fi,21-dihydroxy-3,5,17 (20 -pregnatriene The'methyl 3,7-'dipyrrolidyl-3,5,17(20) [cis] -pregnatrien-Zl-oate obtained according to the method of Preparation 4 was dissolved in about one liter of dry ether and nine grams of lithium aluminum hydride was added thereto. The solution was stirred for 75 minutes and then sixty milliliters of ethyl acetate was slowly added to decompose the excess lithium aluminum hydride, followed by sixty milliliters of water. Heat was evolved bringing the solu- The thus-volatilized solvent was distilled from the mixture. There was thus-produced a concentrated solution containing 3,7-dipyrrolidyl-1lfi,2 1- dihydroxy-3,5 ,17( 20) -[cis]-pregnatriene which can be isolated by separating the ether, drying the solution with anhydrous magnesium sulfate and then distilling the dried solution to dryness.

PREPARATION 6 11,8,21-dihydroxy-4,6,1 7 (20) [cis] -pregnatrien-3-0ne The ether solution of 3,7-dipyrrolidyl-11,8,21-dihydroxy- 3,5,,17(20)-[cis]-pregnatriene obtained according to the method of Preparation 5 was mixed with 400 milliliters of methanol and forty milliliters .of ten percent aqueous sodium hydroxide. The mixture was maintained at forty degrees centigrade for about fifteen minutes and 25 milliliters of acetic acid was then added. After about one hour the solution was made acidic with dilute hydrochloric acid and extracted with methylene chloride. The extract was washed with dilutesodium hydroxide and water and then dried, filtered and distilled to dryness. The residue consisted of 11,6,21-dihydroxy4,6,l7(20) [cis] -pregnatrien-3-0ne.. 1

: PREPARATION 7 1 1 fi-hydroxy-ZI -acetoxy-4,6,1 7 (20 [cis] pregnatrien- 1 3-one. 7

' grams of precipitated steroid was removed by filtration,

Washed with water and dried. After crystallization from acetone the llfi-hydroxy-Zl-aoetoxy- 4,6,l7(20) [cis]- pregnatrien-3-one melted at 177 to 181 degrees centigrade. A recrystallized sample melted at 180 to 182 degrees centigrade, had an [@1 of plusdegrees in acetone and an Calculated for C H O C, 74.58; H, 8.16. Found: C, 74.88; H, 8.22.: a g 7 Similarly, 1 1,8,2 1-dihydroxy-4,6, 17 (20) [cis] -pregnatrien-3-one is converted to other 11,8-hydroxy-21-acyloxy- 4,6,17(20)-[cis]-pregnatrien-3-ones by esterification of theZI-hydroxy group, e.g., by reaction with the appropriate acid anhydride, acid chloride or bromide, ester by ester exchange, acid in the presence of an esterification catalyst, etc. Examples of 1lfi-hydroxy-Z1-acyloxy-4,6, 17(20)-[cis]-pregnatrien-3-ones thus-prepared include those wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid, e.g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, 3-ethylbutyric, hexanoic, heptanoic, octanoic, a cyclic acid, e.g., -3fl-hydroxycholanic, 3 3-hydroxyetiocholanic,

-e.g., succinic, glutaric, pimelic, suberic, a hydroxy acid,

e.g., glycolic, lactic, citric, tartaric, d-rnaleic, salicylic, an aminoacid, e.g., glycine, methylglycine, para-aminosalicylic, para-aminobenzoiq. other hetero-substituted acids, e.g., ethylmercaptoacetic, cyanoacetic, chloroacetic, fluoroacetic, trichloroacetic, trifluoroacetic, thioglycolic, or a heterocyclic acid, e.g., ,B-furylcarboxylic, a-picolinic, nicotinic, or other acyl acid.

EXAMPLE 1 Sodium enolate of Z-ethoxyox'alyl-l119,21-dihydroxy- 4,6,1 7 (20 ['cis] -pregnatriene-3-one A solution of one gram of llfi-hydroxy-Zl-acetoxy- 4,6,l7(20) [cis]-pregnatrien-3-one in sixteen milliliters of tertiary butyl alcohol was heated 'to 63 degrees centigrade. Thereto was added 0.8 milliliter of ethyl oxalate and 0.9 milliliter of. a 25 percent sodium methoxidemethanol solution in a nitrogen atmosphere and with stirring. A precipitate began to form before all of the sodium methoxide solution Was added. The reaction mixture was thereupon cooled to thirty'degrees' centigrade and eighteen milliliters of absolute ether was added. The mixture was thereupon stirred for forty minutes, then filtered, the precipitate collected and washed thoroughly with dry ether. The thus obtained sodium enolate of 2 ethoxyoxalyl 115,21 dihydroxy 4,6,l7(20) [cis]- pregnatrien-3'one weighed 1.15 grams (100 percent yield) and gave a dark brown color with Ferric chloride in aqueous methanol. The ultra-violet spectra of the sodium enolate of 2-ethoxyoxalyl-1l,B,2l-dihydroxy-4,6, l7(20)-[cis]-pregnatrien-3-one was as follows:

Alcohol 6 7: E q=7,025 In N alc. H2804 293=9,375; E350=8,175 In 0.01 N alc. KOH e =14,97s; :1000

EXAMPLE 2 Potassium enolate of 2-meth0xy0xalyl-11[3,21-dihydr0xy- 4,6,1 7 (20 [cis] -pregnatrien-3-0-ne 21 -acetate A solution was prepared containing one gram of 11,9- hydroxy 21 acetoxy 4,6,17(20) [cis] pregnatriem 3-one in 25 milliliters of benzene. This solution was heated to the reflux temperature of about eighty degrees and thereto was added 0.8 milliliter of methyl oxalate and 0.25 gram of potassium hydride suspended in five milliliters of benzene. The mixture Was refluxed under stirring for a period of-two hours and then cooled, filtered,

and the precipitate collected; The thus obtained precipit-ate was washed with three 25-milliliter portions of benzene and dried to give the potassium enolate of 2-methoxy oxalyl 11;? hydroxy 21 acetoxy 4,6,17(20)- [cis] -pregnat1ien-3 -one. 7

' EXAMPLE 3 Refluxing 11B,21-dihydroxy-4,6,17(20) -[cis] -pregnatrien-Z-one 2l-propionate, dissolvedin benzene, with 16 the lithium enolate of Z-butoxyoxalyl-l13,21-dihydroxy- 4,6, 17 (20) [cis] -pregnatrien-3 -one 21-phenylacetate.

(d) Reacting 11fl,21-dihydroxy-4,6,l7(20)-[cis]-pregnatrien-3-one 21-trimethylacetate, dissolved in benzene, with ethyl oxalate in the presence of potassium ethoxide yielded a potassium enolate of 2-ethoxyoxalyl-11;8,21- dihydroxy-4,6,17 (20)-[cis]-pregnatrien-3-one 21-trimethylacetate.

(e) Treating 11B,21-dihydroxy-4,6,17(20)-[cis1-pregnatrien-3-one, dissolved in methanol, with potassium ethoxide and methyl oxalate produced the potassium enolate of Z-methoxyoxalyl-l1fi,21-dihydroxy-4,6,17(20)- [cis] -pregnadien-3 -one.

In the same manner as shown in Examples 2 and 3, treating other 21-esters of 11B,21-dihydroxy4,6,l7(20)- [cis] -pregnatrien-3-one with a lower-alkyl oxalate in the presence of a base such as sodium, potassium or lithium methoxide, ethoxide, propoxide, butoxide, or the like, produces the corresponding alkali metal enolates of the 2 lower alkyl 11,8,21 dihydroxy 4,17(20) [cis]- pregnadien-B-one 21-acylates. Such produced alkali metal enolates of 2-alkoxyoxalyl-1lfl,2l-dihydroxy-4,l7(20)- [cis]-pregnadien-3-one 21 -acylates comprise: the sodium, potassium and lithium enolate of 2-butoxyoxalyl-l 1 8,21- dihydroxy-4,6, 17 (20) [cis] -pregnatrien-3-one 2 l-acetate, 2 amyloxyoxalyl 115,21 dihydroxy 4,6,17(20)- [cis]-pregnatrien-3-one 21-acetate, 2-hexyloxyoxalyl-11B, 2l-dihydroxy-4,6,l7 20) [cis] -pregnatrien-3-one 2l-acetate, 2 heptyloxyoxalyl 115,21 dihydroxy-4,6,17(20)- [cis]-pregnatrien-3-one 21-acetate, 2-octyloxyoxalyl-l1fl, 21-dihydroxy-4,6, 17 20) [cis] -pregnatrien-3 -one 21-aceitate; the sodium, potassium and lithium enolates of Z-methoxyoxalyland 2-ethoxyoxalyl-11,3,21-dihydroxy- 4,6,17 (20) -[cis] -pregnatrien-3-one 21-acylates wherein the acylate group is valerate, isovalerate, hexanoate, heptanoate, octanoate, B-cyclopentylpropionate, phenylpropionate, anisate, dineopentylacet ate, triethylacetate, salicylate, toluate, acid succinate, acid tartrate, acid maleate, chloroacetate, dichloroacetate, trichloroacetate, bromoacetate, iodoacetate, fluoroacetate, tn'fluoroacetate, ortho-bromobenzoate, meta-nitrobenzoate, toluenesulfonate, benzenesulfonate, or the like.

EXAMPLE 4 2-ethoxyoxalyl-2-methyl-I1-B,21-dihydr0xy-4,6,17(20)- [cis] -pregnatrien-3-0ne ,days, water was then added and the reaction mixture was extracted three times with fifty milliliters of methylene chloride. 'The combined methylene chloride extracts were washed with brine, dried and concentrated to-dryness. The yellow residue thus obtained was recrystallized from acetone-skellysolve B hexane's to give pure 2-ethoxyoxalyl- Z-methyl 11p,21 dihydroxy-4,6,17(20)-[cis]-pregnatrien-3-one 21 acetate. a V

- E l L S 2 -.meth0xyoxalyl-Z-methyl-l1B,21-dihydr0xy-4,6, 17(20)-[cis] -pregnatrien-3-0ne 21 -acetate A' mixture of potassium enolate of 2-methoxyoxalyl- 113,21-dihydroxy-4,6,17(20)-[cis]-pregnatrien-3-one, dissolved in acetone,-. was 'reactedwith methyl iodide and potassium carbonate in the manner shown inExample 4. After five days of agitation atroom temperature the reaction mixture was filtered, the filtered cake Washed with four portions of'hot acetone and the combined acetone solution distilled'to leave a residue. The thus obtained residue was recrystallized from acetone Skellysolve B-he'x- 'anes to give pure Z-methoxyoxalyl-2-methyl-l1fl,2l dihydroxy-4,6, 1 7 (20 [cis]-pregnatrien-3-one ZI-acetate.

17 EXAMPLE 6 In the manner shown in Example 5, I

(a) Treating the sodium enolate of2-ethoxyoxalyl- 1l;3,21-dih'ydroxy-4,6, 17 (20)- [cis]-pregnatrien-Ii-one 21- propionate with methyl iodide in the presence of sodium carbonate produced 2-ethoxyoxalyl-2-methyl-l1fi,21:dihydroxy-4,6, 1 7 20) [cis] -pregnatrien'-3-one 2 l-propionate.

(b) Treating the potassium enolate of 2-methoxyoxyalyl-l1,8,21-dihydroxy-4,6,17(20)-[cis]-pregnatrien 3 one 21-benzoate with methyl iodidein the presence of sodium carbonate produced Z-methoxyoxalyl-2-methyl- 11,6,21-dihydroxy-4,6,17(20)-[cis] pregnatrien 3 one- 2l-benzoate.

(c) Treating the potassiumenolate of 2-ethoxyoxalyl- 11fi,21-dihydroxy-4,6,17 (20)-[cis] -pregnatrien-3-one 1 21- phenylacetate with methyl iodide in the presence of sodium carbonate produced 2-ethoxyoxalyl-2-methyh11p, '21-dihydroxy-4,6,17(20)-[cis]-pregnatrien-3-one 2 I-p'henyl-acetate.

(d) Treating the lithium enolate of 2-butoxyoxalyl- 11fl,21-dihydroxy-4,6, 17 (20)-[cis] pregnatrien-3-one 21- acetate with methyl iodide in the presence of sodium-carbonate produced 2-butoxyoxalyl-2-methyl-l1;8;21-dihydroxy-4,6,17(20)-[cis]-pregnatrien-3-one 21-acetate.

(e) Treating the sodium enolate of 2-ethoxyoxalyl- 115,21-dihydroxy-4,6,17(20)-[cis]-pregnatrien 3-one with butyl bromide in the presence of potassium carbonate produced 2-ethoxyoxa1yl 2 butyl-l1,8,21-dihydroxy-4,6, 17(20)-[cis]-pregnatrien-B-one.

(f) Treating the sodium enolate of 2-ethoxyoxalyl- 11 3,21-dihydroxy-4,6,17'(20)-'[cis]-pregnadien-3-one 21- acetate with ethyl iodide in thepresence of potassium-carbonate produced 2-ethoxyoxalyl -.2 'ethyl-l.'1-fl,2l-dihydroxy-4,6, 1 7 (20 [cis] -pregnatrien-3-one 21-acetate.

(g) Treating the sodium enolate of Z-ethoxyoxalyl- E1 1,3,21-dihydroxy-4,6,17(20) -[cis]- pregnatrien-3-.one 2-1- :acetate with propy] iodide in the presence of potassium carbonate produced Z-ethoxyoxalyl-Z-propyl-115,21-dihy- :droxy-4,6,17(20)-[cis]-pregnatrien-3-one 2l-acetate.

(h) Treating the sodium enolate of 2-ethoxyoxalyll1 8,21-dihydroxy-4,6,17(2O)-[cisl-pregnatrien-3-one 72t- :acetate with pentyl iodide in the presence of potassium =:carbonate produced 2-ethoXyoxalyl-2-pentyl-l1,3,21-dihy- \droxy-4,6,17(20)-[cis]-pregnatrien-3-one 2l-ac'etate.

-(i) Treating the sodium enolate of Z-ethoxyoxalyl- 1 15,2l-dihydroxy-4-,6,17(20) -[cis]-pregnatrien-.3-one 2'1- :acetate with hexyl chloride in the presence of potassium carbonate produced 2-ethoXyoxalyl- 2-hexyl-i1lfl,2-1 dihyproxy-4,6, 1 7 (20 [cis] -pregnatrien-3-one 21-acetate.

.(j) Treating the sodium enolate of :2-ethoxyoxalyl 11,8,2l-dihydroxy-4,6,17(20)-[cis]-pregnatrien-3-one 21- :acetate with heptyl iodide in the presence of potassium -.carbonate produced 2-ethoxyoxalyl-2 heptyl-1'1}8,2l-dihyproxy-4,6, 17 (20) [cis] -pregnatrien-3-one 21-acetate.

(k) Treating the sodium enolate of 2-ethoxyoxalyl- 11fi,2l-dihydroxy-4,6,17(20)-pregnatrien-3-one 21-acetate with octyl iodide in the presence ofpotassium carbonate produced 2 ethoxyoxalyl-Z-oetyl-l1;8,21-dihydroxy-4,6, .17(20)- [cis]-pregnatrien-S-one 21-acetate.

(l) Treating the sodium enolate of 2-ethoxyoxalyl v1 l 3,21-dihydroxy-4,6,17(20)-[cis]-pregnatrien-3 one 2'1- acetate with benzyl iodide in the presence ofpotassium carbonate produced 2-ethoXyoxalyl-2 benzyl'-1113,2bdihy- :droxy-4,6, 17 (20 [cis] -pregnatrien-3-one 2 l ace'tate.

(m) Treating the sodium enolate of 2-ethoxyoxalyll 113,21-dihydroxy-4,6,17(20)-t[cis] pregnatrien-3 one '21- :acetate with phenyl iodide in the presence of'pota'ssium carbonate produced 2-ethoxyoXalyl-2-pheny1-116,21 dihydroxy-4,6, 17 (2O [cis] -pregnatrien-3-one 2 l acetate.

In the same manner as shown in'Examp'les 4thrn6,

treating an alkali metal enolate of a Z-lower-alkyloxyoxalyl 11 3,21 dihydroxy-4,6,17(20)- ['cis]=pregnatrien- .3-one 2l-acylates with a lower-alkyl halide preferably a loWer-alkyl halidewherein the alkyl group has from-one I eight carbon'at'oms 'and"thehalogen anfi'atomic'twei'ght between 34 and 130, preferably in the presence of a catalyst such as sodium or potassium carbonate, produces the corresponding 2-lower-alkoxyoxalyl-2-alkyl 1113,21-dihydroxy 4,6,17(20)-[cis] -pregnatrien 3 one 21-acylates, illustratively those 2-lower-alkoxyoxalyl-Z-alkyl-11,8,21- dihydroxy-4,6,17 (20 cis] -pregnatrien-3-one 2l-acylates wherein the alkoxy group is methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, or the like, the alkyl group is methyl, ethyl, propyl, pentyl, hexyl, heptyl, octyl, benzyl, phenyl, or the like, and the acyl groupof the acylate is acetyl, propionayl, butyryl, valeryl, isovaleryl, hexanoyl, heptanoyl, octanoyl, benzoyl, toluenesulfonyl, anisoyl, gallyl, toluyl, chloroacetyl, dichloroacetyl, or the like.

EXAMPLE 7 2-methyl-11fl,21-dihydroxy4,6,1 7(20)- [cis] -pregnatrien-3-one A solution was prepared containing 2.5 grams of 2- ethoxyoxalyl 2 methyl 115,21 dihydroxy-4,6,17(20)- [cis] -pregnatrien-3-one, dissolved in 75 milliliters of methanol. To the solution was added three milliliters of 25 percent sodium methoxide and the mixture was stirred for a period of two hours and twenty minutes in a nitrogen atmosphere. The solution was thereupon diluted with water and extracted with three SO-milliliter portions of methylene chloride. The extracts were washed with water until neutral to phenolphthalein, dried over anhydrous sodium sulfate and evaporated to give a residue. residue was crude Z-methyl-l15,21-dihydroxy-4,6,17'(20)- [cis] pregnatrien-3 -one.

The thus obtained 2-methyl 11,8,21 dihydroxy-4,=6, 17 (20)-[cis]-pregnatrien-3-one was dissolved in ten milliliters of pyridine and five milliliters of acetic anhydride. After standing overnight at room temperature (about. 20- 25 degrees centigrade) the solution was diluted dropwise with water and extracted with ether. The extracts were washed with aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated. The :thus obtained residue, 2.1 grams, was a yellow glassy solid. This product was chromatographed through 50 grams of Florisil collecting fractions of milliliters as follows in Table I:

TABLE. I

Fraction No. Solvent Skellysolve B-hexane-methylene chloride 1:1. Skellysolve B-hexane-methylene chloride 1:1. Acetone-Skellysolve B 5:95. Acetone-Skellysolve B 8:92. Acetone-Skellysolve B 18:82. Acetone-Skellysolve B 30:70.

. Acetone.

Acetone.

Fractions 6 through 17, inclusive, were combined, evaporated and rechromatographed over thirtyigramsof aFlorisil synthetic magnesium silicate .using fractions as' follows in Table II.

TABLE II Volume of Fraction Fraction, Solvent milliliters 1-4 10D Skellysolve'B hexanes.

Acetone-Skellysolve B'-2:98. Acetone-:SkellysolvaB 4:,96. .Acetone-Skellysolve B ,6194. Acetone-Skellysolve B 8:92.

Acetone-Skellysolve B 10:90. Acetone-Skellysolve. -B 14:86. Aeetone-Skellysolve B 20:80. Acetone.

Fractions 11 through 15 were combined and evaporated to give '2-methyl 11 p hydroxy-4,6,17( 20)- [ciskPr gnaalso utilizable. dihydroxy- 4,6,17(20)-[cis]-pregnatrien-3-ones 21-acylates -,e=22,925 and rotation [oz] of plus 150 degrees in chloroofOl'III. a EXAMPLE 8 Z-methyl-l 16,21 dihydroxy-4,6,1 7(20)- [cis] -pregnatrien-S-one In the manner shown in Example 7, treating Z-ethoxyoxalyl 2 methyl-1l6,21-dihydroxy 4,6,l7(20)-pregnatrien-3-one 21-propionate with potassium ethoxide in ethanol solution resulted in 2-methyl-116,21-dihydroxy-4,6, 17 (20) [cis] -pregnatrien-3-one.

Hydrolyzing in the manner shown in Examples 7 and 8, the ,Z-methoxyoxalyl 2 methyl 116,21 dihydroxy-4,6, 17(20)-[cis]-pregnatrien-3-one 21-benzoate, 2 ethoxyoxalyl-Z-methyl-l16,21-dihydroxy 4,6,17(20)[cis] -pregnatrien-3-one 2l-phenylacetate and the 2-butoxyoxalyl-2- methyl 116,21 dihydroxy-4,6,17(20)-[cis1-pregnatrien- 3-one 21-acetate with sodium ethoxide or sodium methoxide in methanol or ethanol solution or with other bases ..such as sodium carbonate,.sodium bicarbonate, potassium carbonate, or the like in aqueous alcoholic solution yielded Z-methyl-l 16,21-dihydroxy-4,6, 17 (20)- [cis] -pregnatrien-B-one.

EXAMPLE 9 v Hydrolyzing in the manner shown in Example 5 with potassium methoxide in ethanol:

(a) 2-ethoxyoxalyl 2 butyl 116,21 dihydroxy-4,6, 17(20)-[cis]-pregnatrien-3-one yielded 2-buty1-116,21-dihydroxy-4,6, 17 (20 [cis] -pregnatrien-3-one;

(b) 2-ethoxyoxalyl 2 ethyl 116,21 dihydroxy-4,6, 17(20)-[cis]-pregnatrien-Ia-one 21-acetate yielded Z-ethyl- 1 16,21-dihydroxy-4,6, 17 20) [cis] -pregnatrien-3-one;

(c) 2-ethoxyoxalyl 2 propyl 116,21 dihydroxy- 4,6,17(20)-[cis] -pregnatrien-3-one yielded 2-propyl-116,

21-dihydroxy-4,6, 17 20) [cis] -pregnatrien-3-one.

(d) 2-ethoxyoxalyl 2 pentyl 116,21 dihydroxyv 4,6,17(20)-[cis]-pregnatrien-S-one 21-acetate yielded 2- pentyl 116,21 dihydroxy-4,6,l7(20)-[cis]-pregnatrien- 3-one.

(e) 2-ethoxyoxalyl 2 hexyl 116,21 dihydroxy-4,6,

17(20)-[cis] -pregnatrien-3-one Zl-acetate yielded Z-hexyl- 1 16,21-dihydroxy-4,6, 17 (20)-[cis] -pregnatrien-3-one.

(f) Z-ethoxyoxalyl 2 heptyl 116,21 dihydroxy-4,6, 17 (20)-[cis]-pregnatrien-3-one 21-acetate yielded 2-hepty1-1 1 6,2 1-dihydroxy-4,6, 17 20 [cis] -pregnatrien-3-one.

(g) 2-ethoxyoxalyl 2 octyl 116,21 dihydroxy-4,6,

' 17 (20)-[cis]-pregnatrien-3-one 2l-acetate yielded 2-octyl- 1-16,21-dihydroxy-4,6,17 (20) [cis] -pregnatrien-3-one.

(h) 2-ethoxyoxalyl 2 benzyl 116,21 dihydroxy- 4,6,17(20)-pregnatrien-3-one 21-acetate yielded 2-benzyl- 116,21-dihydroxy-4,6,17(20)-[cis]-pregnatrien-3-one.

(i) Z-ethoxyoxalyl 2 phenyl 116,21 dihydroxy- 4,6,17(20)-[cisl-pregnatrien-fi-one .2l-acetate yielded 2- phenyl 116,21 dihydroxy-4,6,17(20)-[cis]-pregnatrien- I 3-one'.

'In the same manner as shown in Example 7, the 21- alcohols of 2-lower-alkyl-116,2l-dihydroxy-4,6,17(20)- [cis]-pregnatrien-3-one of Examples7, 8, and 9 can be esterified to give the corresponding 21-esters. Esterification is usually carried out in the manner shown in Example 7, using a solvent such as pyridine or a neutral solvent such as ether, benzene, toluene, or the like, and an esterification reagent such as an anhydride or a chloride or bromide of an organic carboxylic acid respectively of a hydrocarbon carboxylic acid. The anhydrides and halides of organic carboxylic acids or hydrocarbon carboxylic acids useful in the esterification comprise those from one to eight carbon atoms in particular, but those containing up to twelve carbon atoms such as, for example, lauryl, undecylenyl or dineopentylacetyl bromide or' chloride are The thus obtained 2-lower-alkyl-116,21-

comprise the 21-acetate, propionate, cyclopentylpropionate, butyrate, isobutyrate, valerate, isovalerate, h exanoate, heptanoate, octanoate, phenylacetate, benzoate, toluate, trimethylacetate, dineopentylacetate, triethylacetate, chloro-, bromoand iodoor fluoroacetate, trichloroand trifluoroacetate, toluene-sulfonate, benzenesulfonate, nicotinate, 2-furoate, and other acid esters of 2-loweralkyl 116,21 dihydroxy 4,6,17(20) [cis] pregnatrien-Zl-one wherein the lower-alkyl group comprises methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,

hexyl, octyl, phenyl, benzyl, or the like.

ExAMPLn 10 2-methyl-116,21 dihydroxy-4,6,1 7 (20 [cis] -pregnatrien- 3 -one N 283 my, e=24,450

Anal.-Calcd. for C H O +V2 mole of ethyl acetate: C, 74.57; H, 8.86. Found: C, 74.52; H, 8.78 8.90.

EXAMPLE 11 Z-methyl-I 16,17a,21-trihydr0xy-4,6-pregnadien- 3,20-di0ne 21 -acetate A solution was prepared containing 230 milligrams of 2 methyl 116,21 dihydroxy 4,6,17(20) [cis] pregnatrien-3-one 21-acetate, 13-milliliters of tertiary butylalcohol, 0.15 milliliter of pyridine, one milliliter of N- methylmorpholine oxide peroxide (4.4 N in respect to thiosulfate solution) and 0.45 milligram of osmium tetroxide in 0.1 milliliter of tertiary butyl alcohol. The thus prepared solution was allowed to stand at room temperature for a period of 24 hours and thereafter was diluted with water and extracted with methylene chloride. The combined extracts were washed with dilute hydrochloric 'acid, dilute sodium bicarbonate and Water, dried and concentrated to dryness. The residue was chromatographed through 15 grams of Florisil taking fractions as shown in Table III.

TABLE III Volume of Fraction,

Fraction milliliters Solvent 1. B 10190. B 12188. B 14:85. E 20280. B 50250.

Fractions 15 to 18 were combined, dried, and evaporated and the thus obtained residue recrystallized from ethyl acetate ether. The thus obtained Z-methyl-l16,l7e,21-trihydroxyt,6 -pregnadien-3,20--dione 21-acetate had a melting point of 211 to 216 degrees centrigrade, and an ultraviolet absorption, e =23,425. The infrared spectrum indicated that the product is solvatecl. Otherwise, the proposed structure is in agreement with the spectrum.

Anal.--Calcd. for C H O /2 mole EtOAc: C, 68.10;

H, 7.47. Found: C, 68.21; H, 8.25. r

The solvated ,2-methyl-116,17a,2l-trihydroxy-4,6-preg- 7 nadiene-3,20-dione '21-acetate was heated to 100 degrees centigrade over phosphorus pentoxide for a period of eighteen hours to give pure -Z-methyl-I16,17a,21-trihydroxy-4,6-pregnadiene-3,20-dione 2l-acetate..'

in the same manner as shown in Example 11, treating with N-methylmorpholine oxide peroxide and osmium tetroxide in tertiary butyl alcohol in the presence of pyridine:

(a) 2 methyl 115,21 dihydroxy 4,6,17() [cis]- pregnatrien-S-one 2l-acetate yielded 2-methyl-115,17a,2ltrihydroxy-4,6-pregnadiene-3,ZO-dione 21-acetate.

(b) 2 ethyl 115,21 dihydroxy 4,6,17(20) [cis]- pregnatrien-3-one 2l-acetate yielded 2-ethyl-115,17a,21- trihydroxy-4,6-pregnadiene-3,ZO-dione 21-acetate.

(c) 2 propyl 115,21 dihydroxy 4,6,17(20) [cis] pregnatrien-3-one 21-acetate yielded 2-propyl-115,17a,2ltrihydroxy-4,6-pregnadiene-3,20-dione Z-acetate.

(d) 2 isopropyl 115,21 dihydroxy 4,6,17(20)- [cis3-pregnatrien-3-one 21-acetate yielded '2-isopropyl- 1 l5,17a,2 l-trihydroxy-4,6-pregnadiene-3,20-dione 21-acetate.

(e) 2 butyl 115,21 dihydroxy 4,6,17(20) [cis]- pregnatrien-3-one 21-acetate yielded 2-butyl-115,17a,21- trihydroxy-4,6-pregnadiene-3,20-dione 2l-acetate.

(f) 2 pentyl 115,21 dihydroxy 4,6,l7(20) [cis]- pregnatrien-3-one 21-acetate yielded 2-pentyl-115,17u,21- trihydroxy-4,6-pregnadiene-3,20-dione 2-acetate.

(g) 2 hexyl 115,21 dihydroxy 4,6,17(20) [cis]- pregnatrien-3-one 2l-acetate yielded 2-hexyl-115,17a,21- trihydroxy-4,6-pregnadiene-3,20-dione Z-acetate.

(h) 2 heptyl 115,21 dihydroxy 4,6,17(20) [cis]- pregnatrien-3-one 2l-acetate yielded 2-heptyl-115,17a,21- trihydroxy-4,6-pregnadiene-3,20-dione Z-acetate.

(i) 2 octyl 115,21 dihydroxy 4,6,17(20) [cis]- pregnatrien-S-one 21-acetate yielded 2-octyl-1l5,17u,21- trihydroxy-4,6-pregnadiene-3,20-dione 2l-acetate.

(j) 2 benzyl 115,21 dihydroxy 4,6,17(20) [cis]- pregnatrien-3-one 21-acetate yielded 2-benzyl-115,17a,2ltrihydroxy-4,6 l-pregnadiene-3,20-dione 21-acetate.

(k) 2 phenyl 1l5,21-dihydroxy-4,6,l7(20)-[cis]- pregnatrien-B-one 2l-acetate yielded 2-phenyl-115,l7a, 21-trihydroxy-4,6-pregnadiene-3 ,ZO-dione 21-acetate.

(I) 2 methyl l15,21-dihydroxy-4,6,17(20)-[cis]- pregnatrien-3-one 21-propionate yielded 2-methyl-1l5, l7a,2l trihydroxy-4,6-pregnadiene-3,20-dione 21-propionate.

(m) 2 methyl l15,21-dihydroxy-4,6,17(20)-[cislpregnatrien-3-one 21-benzoate yielded 2-m'ethy-l-115,17a, 21-trihydroxy-4,6-pregnadiene 3,20-dione 2l-benzoate.

(n) 2 methyl 115,21-dihydroxy-4,6-,l7(20)-[cis] pregnatrien-B-one 2l-phenylacetate yielded 2-methyl-l15, l7a,21-trihydroxy-4,6-pregnadiene-3,20-dione 21-phenylacetate.

('0) 2 methyl 1l5,2l-dihydroxy-4,6,17(20)-[cis]- pregnatrien-3-one 2l-trimethylacetate yielded Z-methylll5,l7a,21 trihydroxy 4,6-pregnadiene-3,20-dione 21- trimethylacetate.

In the same manner as shown in Example 12, other 2 lower-alkyl-l15,21-dihydroxy-4,6,l7(20)'-pregnatrien- 3-ones may be treated with osmium tetroxide in tertiary butyl alcohol in the presence of pyridine to give the corresponding 2 lower-alkyl-l15,l7a,2l-trihydroxy-4,6- pregnadiene-3,20-dione 21-acylates. Thus obtained acylates include the 2 methyl-115,17u,21-trihydroxy-4,6-

pregnadiene-3,20-dione 2l-acylates wherein the 21-acylate is butyrate, isobutyrate, valerate, isovalerate, hexanoate, heptanoate, octanoate, phenylpropionate, toluate, cinnamate, lactate, acid tartrate, dihydrogencitrate, chloroacetate, bromoacetate, fluoroacetate, iodoacetat'e, dichloroacetate, dineopentylacetate, triethylacetate, or the like.

EXAMPLE l3 A solution of 450 milligrams of2-methyl-ll5,l7a,21-

.trihydroxy-4,6-pregnadiene-3,20-dione ZI-acetate in thirty milliliters of acetone and two milliliters of .water was 22 mixed with 300 milligrams of N-bromoacetamide. After stirring for three hours the reaction mixture was poured into thirty milliliters of water containing 600 milligrams of sodium sulfite and thereafter stirred for a period of one hour. The acetone was distilled at reduced pressure and the solution was extracted with methylene chloride. Evaporation of the solvent and recrystallization yielded 2-methyl-17u,21-dihydroxy-4,6-pregnadiene-3,11, 20-trione 21-acetate.

EXAMPLE 14 2 methyl 1704,21-dihydroxy-4,6-pregnadiene-3,I1,20- trione A solution containing one gram of 2-methyl-17u,21- dihydroxy-4,6-pregnadiene-3,l1,20-trione 21-acetate, 25 milliliters of percent alcohol and one gram of potassium carbonate was refluxed for a period of thirty minutes in a nitrogen atmosphere and thereupon poured into milliliters of ice water. The mixture was then extracted with methylene chloride, the methylene chloride extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to give 2-met hyl-l7u,21-dih\ydroxy-4,6-pregnadiene-3,11,20-trione. Infrared spectrum in chloroform confirmed the structure.

EXAMPLE l5 Z-mPthylhydrocortisone A solution of 1.4 grams of potassium hydroxide (reagent grade, 85 percent), dissolved in .two liters of anhydrous methanol, was admixed with a slurry of two grams of five percent palladium-charcoal catalyst suspended in 800 milliliters of anhydrous methanol, in a 2.5 gallon cylindrical bottom. With vigorous stirring hydrogen was introduced at 1 to 1.5 atmosphere pressure to reduce the catalyst. Then a warm solution of 25 grams of 2 methyl ll5,17ot,21-trihydroxy-4,6-pregnadiene-3,20-dione 21-acetate, dissolved in 950 milliliters of methanol Was added. To the resulting mixture 1 to 1.1 mole equivalent of hydrogen was introduced at about 1 to 1.5 atmospheres pressure using vigorous stirring. When the selective hydrogenation was complete, the catalyst was removed by filtration and the filtrate acidified with two milliliters of acetic acid, and the solvent distilled under reduced pressure. The resulting Z-methylhydrocortisone was extracted with milliliters of hot ethyl acetate. The insoluble potassium acetate was removed by filtration and the filtrate was allowed to cool to room temperature (25 degrees centigrade) and finally refrigerated to five to ten degrees centigrade, The crystalline product which precipitated from the filtrate, was

EXAMPLE 16 Z-methylcortisone In the same manner as shown in Example 15, Z-methyl- 17:2,2-1 dihydroxy 4,6 pregnadiene-3,11,20 trione 21- acetate was reduced with hydrogen in the presence of a palladium charcoal catalyst and potassium hydroxide under the conditions shown in Example 15 to give 2- methyl 1711,21 dihydroxy 4-pregnene-3,11,20-trione Z-methylcortisone).

In the same manner as in Examples 15 and 16, 2-methyl-hydrocortisone and Z-methylcortisone and other 2- loWer-alkyl cortisone and hydrocortisone are prepared by hydrogenating the 6,7 -double bond of the corresponding 2- lower alkyl 115,17a,21-trihydroxy-6-pregnadiene-3,20- dione or 2-lower-alkyl-17a,21-dihydroxy-4,6-pregnadiene- 3,11,20-trione.

Esterification of the Z-methylhydrocortisone and cortisone by standard methods, such as treating the 2-met liyl 2 methyl 17a,2l-dihydr0xy-4,6,9(I1)-pregnatriene-3,

ZO-dione 21 -acetate (Z-methyl-I7u-hydr0xy-21-acetoxy- 4,6,9 (1 1 -pregnatriene-3,20-dione) A mixture of one gram of 2-methyl-1l fi,l7a-trihydroxy- 4,6-pregnadiene-3,20-dione Zl-acetate, 60 milligrams of N-bromoacetamide and six milliliters of pyridine was stirred in the dark for a period of five minutes. The mixture was then cooled in an ice-water bath and a stream of sulfur dioxide was directed under the surface of the stirred mixture until a negative potassium iodidestarch test was obtained. Fifty milliliters of water was then added to the mixture and the mixture was main tained at about five degrees centigrade for thirty minutes. The precipitated white solid was filtered, washed with water and dried under vacuum. After recrystallization from acetone there was obtained pure 2-methyl-l7a,21- dihydroxy-4,6,9( 1l)-pregnatriene-3,20-dione ZI-acetate. Using instead of the 21-acetate of 2-methyl-llli,l7u,2ltrihydroxy-4,6-pregnadiene-3,20-dione the propionate, the butyrate, the benzoate, and the like, the corresponding 2 methyl 17a,21-dihydroxy-4,6,9(11)-pregnatrien-3- one 2l-propionate, butyrate, benzoate, and the like, is obtained.

Hydrolyzing in a nitrogen atmosphere with potassium carbonate in methanol or ethanol as shown in Example 14, 2 methyl-17a,2l-dihydroxy-4,6,9(l1)-pregnatriene- .3,20-dione 2l-acetate produces the corresponding free alcohol, 2 methyl 17a,21-dihydroxy-4,6,9(11)-pregnatriene-3,2O-dione.

EXAMPLE 18 In the manner shown in Example 17, treating a 2-loweralkyl 1l/3,17a,2l trihydroxy-4,6-pregnadiene-3,20'dione ZI-acylate with N-bromoacetamide in pyridine solution gives the corresponding 2-lower-alkyl-llfi-hypohalo- 17,2l-dihydroxy-4,6-pregnadiene-3,ZO-dione 21-acylate which when decomposed with sulfur dioxide gave the corresponding 2 lower-alkyl-l7u,21-dihydroxy-4,6,9(ll)- pregnatrien-3,20-dione ZI-acylate.

Thus from:

(a) 2 ethyl ll,8.l7a.2l-trihydroxy-4,G-pregnadiene- 3,20-dione 2l-acetate was obtained 2-ethyl-l7oe,21-dihydroxy-4,6,9(11)-pregnatriene-3,20-dione 21-acetate.

(b) 2 propyl-llB,l7a,21-trihydroxy-4,6-pregnadiene- 3,20-dione 21-acetate was obtained 2propyl-17a,21-dihy- -droxy-4,6,9(11)-pregnatriene3,20-dione 2l-acetatev (c) 2 benzyl 11,3,17cx,2l trihydroxy 4,6 -pregnadiene-3,20-dione Zl-acetate was obtained 2-benzyl-17a,21- dihydroxy-4,6,9(l1)-pregnatriene-3,20-dione 21-acetate.

(d) 2 butyl 11,8, 170:,21 trihydroxy 4,6 -pregna-' diene-3,20-dione 21-propionate was obtained 2-butyl-l7a, 21-dihydroxy-4,6,9( l1)-pregnadiene 3,20 dione 21-propionate. p

(e) 2 h'exyl 115,170121 trihydroxy 4,6 pregnadiene-3,20-dione 2l-phenylpropionate was obtained 2- hexyl-17tx,21 dihydroxy 4,6,9( 11) pregnatriene 3,20-

dione ZI-phenylpropionate.

(f) 2 octyl llfi,l7ot,2l -trihydroxy 4,6 -pregnadiene-3,20-dione 21-hexanoate was obtained 2-octyl-17a, 21-dihydroxy-4,6,9( 1l)-pregnatriene-3,2'0 dione 21-hexanoate.

' EXAMPLE 19 2-mez'hyl-9a-br0m0-115,17a,2J-trihydr0xy-4,6- pregnadiene-iZO-dion 21 acetate A solution of one gram of 2-'nethyl-Hall-dihydroxy- 4,6,9(ll)-pregnatriene-3,20-dione Zl-acetate, dissolved in forty milliliters of methylene chloride, was reacted with vtwo milliliters of 71' percent perchloric acid in twenty milliliters of water and thereto was added 400 milli- 24 grams of N-bromoacetate in 109 milliliters of tertiary butyl alcohol. The solution was maintained at room temperature for a period of thirty minutes and then mixed with a solution of 050 gram of sodium sulfite in 24 milliliters of water. The mixture was distilled at reduced pressure and the residual solution became cloudy. The product was then precipitated by the addition of 200 milliliters of a mixture of ice and water. The white crystalline precipitate of 2-rnethyl-9a-bromo-11 8,171,21- trihydroxy-4,6-pregnadiene-3,ZO-dione 2l-acetate was filtered, washed with water and then dried at room temperature in a vacuum. Recrystallization from a mixture of acetone and Skellysolve B gave pure 2-methyl-9ubromo-l lfl, l7a,21-trihydroxy-4,6-pregnadiene-3,2O dione 2l-acetate (2-methyl-9u-bromo 1113,17a dihydroxy 21- acetoxyl,6-pregnadiene-3,ZO-dione) EXAMPLE 2O 2-ethyl-9a-chl0r0-11BJ 7a,21-trihydroxy'-4,6-pregnadiene- 3,20-dione 21 -acetate A mixture of one gram of 2-ethyl-17a,2l-dihydroxy- 4,6,9(1l)-pregnatriene-3,20-dione 2l-acetate, dissolved in fifty milliliters of methylene chloride, was reacted with a solution of two milliliters of 71 percent perchloric acid in ten milliliters of water and thereto was added N- chlorosuccinimide in milliliters of tertiary butyl al- In the same manner as shown in Examples 19 and 20, reacting 2-lower-alkyl 17a,2l dihydroxy-4,6,9(ll)-pregnatriene-3,20-dione 21-acylate in solution with a N-halo acid amide in the presence of acid (to produce in situ a hypohalous acid) yields the corresponding 2-loweralkyl-9ot-halo-ll 8,l7a,2l trihydroxy 4,6 pregnadiene- 3,20-dione ZI-acylate wherein the halogen atom in the S a-position has an atomic weight between 34 and 130. Representative 9a-halo compounds thus obtained are: the 2-propyl 9a halo-11B,l701,21-trihydroxy-4,6-pregnadiene-3,20-dione Zl-acetate, the 2-benzyl-9a-halo-l1,3,l7a, 2l-trihydroxy-4,6-pregnadiene-3,ZO-dione 21-acetate, the 2-butyl-9u-halo-113,17a,21-trihydroxy 4,6 pregnadiene- 3,20-dione ZI-propionate, the 2-h'exyl-9o -halo-l15,111,21-

dihydroxy-4,6-pregnadiene-3,ZO-dione 2l-phenylpropionate, the 2-octyl-9a-halorl16,17a,2l-trihydroxy-4,6-pregnadiene-3,20 dio'ne 21-octanoate wherein the halo atom is bromo, chloro, or iodo.

EXAMPLE 22 Z-niethyl-Qa-bromo-I 70,21 -d ihydroxy-4 ,6 -pregnad iene- 3,11,20-trione ZI-acetate A solution was prepared containing one half gram of 2-methyl-11B,17a,2l trihydroxy-4,fi-pregnadiene 3,20- dione 2l-acetate, dissolved in five milliliters of glacial acetic acid. To this solution was added 0.3 gram of chromic anhydride, dissolved in two milliliters of acetic The thus obtained solution was maintained at room temperature for a period of three hours. Thereafter one milliliter of methanol was added, the solution was shaken and poured into twenty milliliters of ice water. Sodium bicarbonate solution was added to neutralizelthe solution and the solution was then filtered to give a crude material which was recrystallized from acetone-Skellysolve B hexanes to give 2- methyl-9a-b10m0 :,21 dihydroxy 4,6 pregnadienei.3,l1,20-trione 21-acetate. V

In the same manner as shown in Example 22, oxidizing 2-ethyl 9a chloro 11B,l7oc,21 -trihydroxy 4,6-pregnadiene-3,20-dione 2l-acetate with chromic acid in acetic acid solution produces the corresponding Z-CthYI-9ccchloro-17a;1-dihydroxy-4,6-pregnadiene 3,11,20-trione 2l-acetate.

In the same manner as shown in Examples 22 and 23, other 2-lower-alkyl-l7a,21-dihydroxy-4,6-pregnadiene-3, 11,20 trione 2l-acylates are prepared by oxidizing the corresponding 2-lower-alkyl 11B,l7a,21 trihydroxy-4,6- pregnadiene-3,20-dione Zl-acylates. Representative compounds thus obtained comprise the 2-lower alkyl-17a,21- dihydroxy 4,6 pregnadiene 3,11,20 trione 21-acylates wherein the alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, phenyl, benzyl, or the like, and wherein the acylate may be acetate, propionate, butyrate, benzoate, phenylpropionate, phenylacetate, anisate, nicotinate, or the like.

I-Iydrolyzing 2-methyl-9aromo-l7a,21-dihydroxy-4,6- pregnadiene-3,11,20trione 21-acetate with, dilute (five percent) sulfuric acid in ethanol under nitrogen atmosphere produces the corresponding free diol, 2-methyl-9ubromo-17a,21dihydroxy-4,6-pregnadiene-3,1 1,20-trione.

In the same manner as shown in Example 15, hydrogenation of 2 methyl 90c bromo "1701,21 dihydroxy- 4,'6-pregnadiene-3,11,20-trione 2l-acetate with hydrogen and palladium charcoal catalyst in the presence of an alkali hydroxide produces 2-methyl-9a-bromo-l7a,21-dihydroxy 4 pregnene 3,11,20 trione (2 methyl 9abromocortisone). Hydrogenating 2-alkylated 9a-Chl0r0 or 90: iodo l7u,21 dihydroxy 4,6 pregnadiene- 3,11,20-trione acylates in the same manner as shown in Example 15, the chloro or iodo compounds of 2-loweralkyl cortisone can be made.

In the same manner hydrogenating 2-lower-alkyl-9ahalo 11fl,17o,2l trihydroxy 4,6 -.pregnadiene 3,20- dione 21-acylate, dissolved in an organic solvent such as methanol, ethanol, or the like, with hydrogen and a palladium catalyst in the presence of an alkali hydroxide produces the corresponding 2-lower-alkyl-9a-halo-1lfi, 17a,21 trihydroxy 4 -.pregnene 3,20 dione, wherein the lower alkyl group and the halo group are defined as in the preceding.

Treating 2-lower-alkyl-9a-halohydrocortisone, thus ob- 'tained with hydrocarbon carboxylic acid halides or anhydrides in pyridine solution, produces 'the corresponding 2 lower alkyl 9a halohydrocortisone 21 esters,

such as 2 methyl 9a bromohydrocortisone 21 acetate, 2-methyl-9a-chlorohydrocortisone 2l-propionate, 2- ethyl-9u-bromohydrocortisone 21-acetate, 2-methyl-9achlorohydrocortisone 21-benzoate, and the like.

EXAMPLE 24 2 methyl 95,11 8 epoxy 17a,21 dihydroxy 4, 6-

pregnaa'iene 3,20 dione --21 acetate (2- methyl 95,

11 3 epoxy 17a hydroxy 21 acetoxy 4,6 pregnadiene-3,20-dine) A mixture of 0.5 gram of 2-methyl-9u-bromo-l1,8,17u, 21 trihydroxy 4,6 pregnadiene 3,20 dione 21 acetate, 0.5 gram of anhydrous potassium acetate and twenty milliliters of acetone was heated at its refluxing temperature for a period of five hours. The mixture, cooled to room temperature, was thereupon poured into water and extracted with methylene chloride. The methylene chloride extracts were dried over anhydrous sodium sulfate and then evaporated. The thus obtained residue was re crystallized from acetone and Skellysolve B three times to give 2 methyl 9 8,115 epoxy 170:,21 dihydroxy- 4,6-pregnadiene-3,20-dione 2l-acetate.

26 EXAMPLE 25 2-ethyl-9fi,11,B-epoxy--1 7a,21-dihydr0xy-4 ,6- pregnadiene-3,20-dione 21 -acetate In the same manner as shown in Example 24, 2-ethyl-' c chloro 1l,8,17a,2l trihydroxy 4,6 pregnadiene- 3,20 -'dione 21-acetate was heated with anhydrous potas' sium acetate in acetone solution to give 2-ethyl-9,6,1l/3* epoxy l7a,2l dihydroxy 4,6 pregnadiene 3,20 dione 2l-acetate.

Treating in the manner shown in Examples 24 and '25, 2 lower alkyl 90c halo 11B,l7a,21 trihydroxy- 4,6-pregnadiene-3,20-dione 2l-acylates with anhydrous potassium acetate or anhydrous sodium acetate in an anhydrous solvent such as acetone, dioxane, tertiary butyl alcohol, chloroform or the like at a temperature between fifty degrees and the boiling point of the solvent produces the corresponding 2 lower alkyl 95,11 8 epoxy :,21- dihydroxy 4,6 pregnadiene 3,20 dione 2'1 -'acylates. As starting compounds those 2-lower-alkyl-9a-halo-11,9, l7a,21 trihydroxy 4,6 pregnadiene 3,20 dione 21- acylates are useful in which the halo atom is of atomic weight 34 to 130, wherein the alkyl group contains from one to eight carbon atoms and wherein the acyl group of the acylate is of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

EXAMPLE 26 2 methyl 9a fluoro 11fl,17oc,2] trihydroxy 4,6- pregnadiene 3,20 dione 21 acetate (2 methyl- 9a. fluoro 11fi,17oc dihydroxy 21 acetaxy 4,6- pregnadiene-3,20-dione) One gram of 2-methyl-95,lIii-epoxy-17a,21-dihydroxy- 4,6-pregnadiene-3,20-dione 21-acetate, dissolved in 'fifty milliliters of methylene chloride, was treated with five milliliters of 48 percent hydrofluoric acid and 0.5 milliliter of 71 percent perchloric acid at room temperature. The mixture was stirred vigorously for a period of six hours and then poured into an excess of cold aqueous five percent sodium bicarbonate solution. The methylene chloride layer was separated, dried with anhydrous sodium sulfate and thereupon evaporated to give a dry residue of 2 methyl 90c fluoro 11,8,l7a,21 trihydroxy 4,6 pregnadiene 3,20 dione 21 acetate. The material was purified by recrystallization from acetone and Skellysolve B hexanes and the thus purified Z-methyl- 9o: fluoro 1lfi,17a,2l trihydroxy 4,6 pregnadiene- 3,20-dione 21-acetate showed an infrared spectrum in chloroform identical to the one postulated for the proposed compound.

EXAMPLE 27 2-ethyl-9a-flaor0-11fl,17a,21-trihydr0xy-4,6- pregnadiene-3,20-dione 21 -benz0ate In the same manner as shown in Example 26, reacting 2 ethyl 9,6,11 3 epoxy 170:,21 dihydroxy 4,6- pregnadiene-3,20-dione 21-benzoate, with hydrofluoric acid in methylene chloride solution in the presence of a strong acid such as perchloric'acid produced 2-ethyl-9afluoro 11 ,8,17a,21 trihydroxy 4,6 pregnadiene 3,20- dione 21-benzoate.

EXAMPLE 28 In the same manner as shown in Example 27, treating with hydrofluoric acid in methylene chloride in the presence of perchloric acid.

(a) 2 methyl 918,115 epoxy 17,21 dihydroxy- 4,6-pregnadiene-3,20-dione 2l-propionate produced 2- methyl 9oz fluoro 11B,17a,21 trihydroxy 4,6 pregnadiene-3,20-dione 21-propionate. 7

(b) 2 propyl 95,11 8 epoxy 1711,21 dihydroxy- 4,6-pregnadiene-3,20-dione 21-butyrate produced 2-propyl- 9a fluoro 11,B,17oc,21 trihydroxy 4,6 pregnadiene- 3,20-dione 2l-butyrate.

pregnadiene-3,20-dione 21-phenylpropionate.

(f) 2 octyl 95,115 epoxy 170:,21 dihydroxy- 4,6-pregnadiene-3,20-dione ZI-heXanoate produces 2-octyl 9a fluoro 115,17a,21 trihydroxy 4,6 pregnadiene-3,20-dione 2l-hexanoate.

EXAMPLE 29 2-methyl-9ot-i0d0-I 15,1 7d,.21 -trihydroxy-4 ,6 pregn adiene-3,20-dione 21 -acetate In the same manner as shown in Example 26, Z-methyl- 95,115 epoxy 170:,21 dihydroxy 4,6 pregnadiene- 3,20-dione 2l-acetate was dissolved in methylene chloride and reacted with a solution of hydriodic acid in the presence of one percent of perchloric acid calculated on the total volume of solution to give 2-methyl-9oc-iodo- 115,17a,21 trihydroxy 4,6 pregnadiene 3,20-dione 21-acetate.

In the same manner as shown in Examples 26 through 29, treating 2 lower alkyl 95,115 epoxy 1701,21- dihydroxy 4,6 pregnadiene 3,20 dione 21 acylate wherein the 2-lower-alkyl group is selected from methyl, ethyl, propyl, butyl, hexyl, heptyl, octyl, phenyl, and benzyl and the like and wherein the acyl group of the acylate is selected from organic carboxylic acids, preferably hydrocarbon carboxylic acids containing from one to eight carbon atoms, inclusive, with hydrogen halide in the presence of a strong mineral acid such as perchloric, sulfuric acid or a benzenesulfonic acid, illustratively toluenesulfonic acid, produces the corresponding 2-loweralkyl 9a halo 11B,17 x,21 trihydroxy 4,6 pregnadiene-3,20-dione 21-acylate wherein the halogen atom has an atomic weight from 17 to 130, inclusive.

EXAMPLE 30 2-methyl-9u-flu0r0-115,170:,21-trihydroxy-4,6-pregnadiene-3,20-dione I through the solution for a period of ten minutes, The

thus obtained mixture is heated in a nitrogen atmosphere to reflux for a period of forty minutes and thereafter cooled and poured into 200 milliliters of cracked ice. The thus obtained solution was extracted with two S O-milliliter portions of methylene chloride. The methylene chloride extracts were dried, evaporated, and the 'residuewas V recrystallized from Skellysolve B hexanes-ac'etone to give pure 2-methyl-9a-fiuoro-1l5,l70;,21-trihydroxy-4,6-pregnadiene-3,20-dione.

EXAMPLE 31 2-methyl-9a-flu0ro-1 711,21dihydroxy-4,d pregnadiene- 3,1 1,20-trione 21-acetate A mixture was prepared containing 0.5 gram of 2- methyl 9 fluoro 115,17a,21' trihydroxy-4, 6-pregnadiene-3,20-dione 21-acetate, 0.2 gram of lchrornic au- 28 hyride, ten milliliters of glacial acetic acid and one-half milliliter of water. This mixture was stirred and thereupon maintained eight hours at room temperature. Thereafter the mixture was poured into fifty milliliters of ice water and neutralized by the addition of dilute sodium hydroxide. The precipitate thus obtained was collected on a filter and recrystallized from ethyl acetone .and Skellysolve B hexanes, three times, to give Z-methyl- 9a-fluorol7a,2l-dihydroxy 4,6 pregnadiene-3,l1,20-trione ZI-acetone (2-methyl-9a-fluoro17m-hydroxy-2l-acetoxy-4,6-pregnadiene-3,11,20-trione) EXAMPLE 32 V In the same manner given in Example 31, oxidizing in acetic acid solution with chromic anhydride in the presence of a small amount of water:

(a) 2 ethyl 9a fluoro 1l5,17x,21 trihydroxy- 4,6-pregnadiene-3,20-dione 21-benzoate produces Z-ethyl- 9a-fluoro 17oz,21 dihydroxy 4,6 pregnadiene-3,l1,20- trione 2l-benzoate.

(b) 2 methyl c fluoro 115,17a,21 trihydroxy- 4,6-pregnadiene-3,20-dione 21-propionate produced 2- methyl 9oz fluoro 1704,21 dihydroxy 4,6 pregnadiene-3, 1 1,20-trione 21-propionate.

(c) 2 propyl 9a fluoro 115,17a,21 trihydroxy- 4,6-pregnadiene-3,20-dione 21-butyrate produced 2-propyl 9oz fluoro :,21 dihydroxy 4,6 pregnadiene- 3,11,20-trione 2l-butyrate.

,(d) 2 benzyl 9a fluoro 11B,17oc,21 trihydroxy- 4,6-pregnadiene-3,20-dione 21-valerate produces 2-benzyl- 9oz fluoro 170;,21 dihydroxy 4,6 pregnadiene 3,11, 20-trione 21 valerate.

(e) 2 butyl 9a fluoro 115,17a,21 trihydroxy-4,6- pregnadiene-3,20-dione 21-propionate produces Z-butyl- 90c fluoro -17u,21 dihydroxy 4,6 pregnadiene 3,11, 20-trione 2l-propionate. I

(f) 2 hexyl 90c fluoro 115,17a,21 trihydroxy- 4,6-pregnadiene-3,20-dione 21-phenylpropionate produces 2 hexyl 9a fluoro 17oc,2l dihydroxy 4,6 pregnadiene-3,l1,20-trione 2l-phenylpropionate.

(g) 2 octyl 9a fluoro 11fl,17ot,21 trihydroxy 4,6- pregnadiene-3,20-dione 2l-hexanoate produces 2-octyl-9oafluoro 1704,21 dihydroxy 4,6 pregnadiene 3,11,20- trione 21-hexan0ate.

' EXAMPLE 33 sixty milligrams of potassium hydroxide in 300'mi1liliters -of anhydrous methanol was admixed with 0.1 gram of five percentpalladium-charcoal catalyst suspended in fifty milliliters of anhydrous methanol; This solution was hydrogenated at one to 1.5 atmospheres pressure as shown in Example 15, at room temperature. After, the selective hydrogenation was'complete, the mixture was filtered and evaporated to give a residueI. The residue was extracted with methylene chloride to separate the potassium hydroxide and the extracts were evaporated to give a residue 11. This residue II was dissolved-in a mixture of five milliliters of acetic anhydride and five milliliters ofrpyridiner The thus. obtained solution was allowed to stand at room temperature for a period oftwo hours and then poured into excess water. The thus obtained precipitate was collected on filter and. recrystallized from ethyl acetate-Skellysolve B hexanes gave 2-methyl- 9a-fluorohydrocortisone acetate of melting point 225 to 228 degrees centigrade.

Treating the solution of 2-methyl-9a-fluorohydrocortisone (residue II of above) in pyridine with acyl halide or acid anhydride of an organic carboxylic acid preferably of a hydrocarbon carboxylic acid is productive of other 21-esters of 2-methyl-9u-fluorohydrocortisone such as illustratively the propionate, the butyrate, the valerate, the hexanoate, the benzoate, the phenylacetate, the phenylpropionate, the 2-furoate, the B-cyclopentylpropionate, or the like.

EXAMPLE 35 In the same manner as shown in Example 34, hydrogenating with hydrogen and palladium charcoal in methanolic potassium solution 2-methyl-9a-fluoro-17u,21- dihydroxy-4,6-pregnadiene-3,11,20-trione ZI-acetate yielded the 2-methyl-9a-fluoro-l711,21-dihydroxy-4,6-pregnadiene-3,11,20-trione (2-methyl-9a-fluoro cortisone) which can be esterified with acetic anhydride in pyridine to yield 2-methyl-9a-fiuorocortisone 21-acetate.

In the same manner as shown in Examples 34 and 35, selectively hydrogenating 2-lower-alkyl-9a-fluoro-11,8, 17,21-trihydroxy-4,6-pregnadiene-3,ZO-dione or 2-loweralkyl-9a-fluoro-17a,21-dihydroxy 4,6 pregnadiene-3,1 1, 20-trione 21-acylates wherein the lower-alkyl group has from one to eight carbon atoms, inclusive, and the acyl group is of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, produces the corresponding 2-lower-alkyl-9a-fiuorohydrocortisone and 2-lower-alkyl-9a-fluorocortisone.

Vigorous esterification procedures at high temperatures, above seventy degrees centigrade, give the triacylates of 2-methyl-9a-fluorohydrocortisone wherein the 115, the 17m, and the 21-position are esterified. Vigorous esterification conditions used on 2-lower-alkyl-9a-fluorocortisone produces the corresponding diester that is 2- lower-alkyl-9a-fluorocortisone 17a,21-diacylates, which are active adrenocortical hormones with prolonged action.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

'1. A compound selected from the group consisting of 2a-lower-alkyl-11fl,17a,21 trihydroxy-4,6-pregnadiene-3, 20-dione and 2a-lower-alkyl-1 1fl,17a-dihydroxy-21-acyl oxy-4,6-pregnadiene-3,20-dione wherein the lower alkyl radical contains from one to eight carbon atoms, inclusive, and the acyl group of acyloxy is of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

2. Zea-methyl 11,8,17a,21 trihydroxy-4,6-pregnadiene- 3,20-dione.

3. Zea-methyl 11,8,17a,21 trihydroxy-4,6-pregnadiene- 3,20-dione 21-acetate.

4. A compound selected from the group consisting of 2a-1ower-alkyl-9a-halo-1lfl,17a,21-trihydroxy 4,6 pregnadiene-3,20-dione and 2a-lower-alkyl-9u-halo-llfl,l7adihydroxy-21-acyloxy-4,6-pregnadiene-3,20-dione wherein the lower-alkyl radical contains from one to eight carbon atoms, inclusive, the acyl group of acyloxy is of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, and the halo atoms are of atomic weight 17 through 130.

5 2a-methyl-9a-fluoro-l1B,17a,21-trihydroxy-4,6-preg nadiene-3,20-dione.

6. 2u-methyl-9a-fluoro-l1,9,17a,2l-trihydroxy-4,6-pregnadiene-3,20-dione 21-acetate.

7. 2a-methyl-9a-fiuoro-17a,21-dihydroxy 4,6 pregnadiene-3,1 1,20-trione.

8. 2a-methyl-9a-fluoro-17u,21-dihydroxy 4,6 pregnadiene-3,1 1,20-trione 21-acetate.

References Cited in the file of this patent UNITED STATES PATENTS 2,738,348 Colton Mar. 13, 1956 2,739,974 Colton Mar. 27, 1956 2,797,229 Ralls June 25, 1957 2,848,464 Fried Aug. 19, 1958 OTHER REFERENCES Journal of American Chemical Society, vol. (1953), pages 5923. Sondheimer et al.

Journal of American Chemical Society, vol. 77 (1955), page 6401, relied on. Hogg et al.

Hogg et al.:, J.A.C.S. 77, Dec. 5, 1955, pages 6401- 6402.

UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No. 2 985 67l May 23 1961 J Allen Campbell et alu It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 5 line 26 for "(6l 65 CO) read (62%5 in; column 7 line 34L for "4 6 l7(20)=[20] read me l 6 l7(20)== [01s] column l0 line 19 for 'dicethylhydantoin" read dimethylhydantoin line'ZL for triphydroxy read trihydroxy column 12 line 51 for Methyl 3 ll diketo= 6-bromo l l'Z(2O)-{cis]=pregnadien 2l=oate read Methyl 3= acetoxyllketo3(,5 l7(2O)=[cis]-=pregnatrien 2l==oate column 1/8 line 11 for"propionayl" read me propionyl column 21 line 37 for numeral "l l read 4 6 column 28 line 10 ior"acetone" read we acetate column 30 line 42 for "5923" read 5932 Signed and sealed this 24th day of October 19610 (SEAL) Attest:

ERNEST W. SWIDER DAVID La LADD Attesting Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 2A-LOWER-ALKYL-11B,17A,21 - TRIHYDROXY-4,6-PREGNADIENE-3, 20-DIONE AND 2A-LOWER-ALKYL-11B,17A-DIHYDROXY-21-ACYLOXY-4,6-PREGNADIENE-3,20-DIONE WHEREIN THE LOWER ALKYL RADICAL CONTAINS FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE, AND THE ACYL GROUP OF ACYLOXY IS OF A HYDROCARBON CARBOXYLIC ACID CONTAINING FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE. 